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1. Outcomes following switching from etanercept originator to etanercept biosimilar in 1024 patients with RA: a matched-analysis of the BSRBR-RA.

Author

Kearsley-Fleet, Lianne, Rokad, Aasiyah, Tsoi, Man-Fung, Zhao, Sizheng Steven, Lunt, Mark, Watson, Kath D, Group, BSRBR-RA Contributors, and Hyrich, Kimme L

Subjects
THERAPEUTICS, DISEASE duration, RESEARCH funding, RHEUMATOID arthritis, SEX distribution, TREATMENT duration, SYMPTOMS, TREATMENT effectiveness, AGE distribution, DESCRIPTIVE statistics, ETANERCEPT, DRUG monitoring, LONGITUDINAL method, BIOSIMILARS, COMPARATIVE studies, SURVIVAL analysis (Biometry), CONFIDENCE intervals, PROPORTIONAL hazards models
Abstract

Objectives Adults with RA are being switched from etanercept originator to biosimilar in non-medical/cost-saving switching. This analysis aims to investigate outcomes in these patients, including (i) drug survival and (ii) disease activity at 6 months and 12 months, compared with those who remain on the originator. Methods Using BSRBR-RA, those who switched directly from etanercept originator to biosimilar were identified and matched to patients receiving the originator, based on gender, age, disease duration and originator start year. Drug survival was calculated; Cox-proportional hazard models assessed differences in drug persistence between those who switched vs remaining on originator. Change in DAS28 after 6 months and 12 months was compared between cohorts. Multiple imputation was used. Results A total of 1024 adults with RA switching from etanercept originator to biosimilar were included, with a matched cohort of patients remaining on the originator. Patients who switched onto a biosimilar product were no more likely to discontinue etanercept treatment vs those who remained on the originator; hazard ratio 1.06 (95%CI 0.89–1.26), with 65% of patients remaining on treatment at three years. Ninety-five (9%) patients switched back to the originator within the first year. After 6 months and 12 months, biosimilar patients were no more likely to have a worsening of DAS28 (>0.6 units) compared with those who remained on the originator. Conclusions This is the largest matched comparative effectiveness analysis showing patients switching from etanercept originator to biosimilar appearing to do just as well with regard to disease activity and drug persistence compared with those who remained on the originator. These data will be reassuring to clinicians and patients regarding non-medical switching. [ABSTRACT FROM AUTHOR]

Published
2024
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2. Evaluation of serious infections, including Mycobacterium tuberculosis, during treatment with biologic disease-modifying anti-rheumatic drugs: does line of therapy matter?

Author

Lauper, Kim, Kearsley-Fleet, Lianne, Galloway, James B, Watson, Kath D, Group, BSRBR-RA Contributors, Hyrich, Kimme L, and Lunt, Mark

Subjects
BIOTHERAPY, DRUG side effects, DATA analysis, RESEARCH funding, SCIENTIFIC observation, ANTIRHEUMATIC agents, DESCRIPTIVE statistics, LONGITUDINAL method, ETANERCEPT, ADALIMUMAB, STATISTICS, COMPARATIVE studies, CONFIDENCE intervals, INFLIXIMAB, DATA analysis software, HEALTH outcome assessment, MYCOBACTERIUM tuberculosis, PROPORTIONAL hazards models, DISEASE incidence, PHARMACODYNAMICS
Abstract

Objectives This study aimed to evaluate if and how the incidence of serious infection (SI) and active tuberculosis (TB) differ among seven biologic DMARDs (bDMARDs) in patients with RA considering the line of therapy. Methods Patients with RA from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) cohort who initiated etanercept, certolizumab, infliximab, adalimumab, abatacept, rituximab or tocilizumab from the first to fifth line of therapy were included. Follow-up extended up to 3 years. The primary outcome was SI and the secondary outcome was TB. Event rates were calculated and compared using Cox proportional hazards models, controlling for confounding with inverse probability of treatment weights. Comparisons were made overall and stratified by line of therapy. Sensitivity analysis was restricted to all treatment courses from 2009 (tocilizumab availability) until the end of the study (2018). Results Among 33 897 treatment courses (62 513 patient-years) the incidence of SI was 4.4/100 patient-years (95% CI 4.2, 4.5). After adjustment, hazards ratios (HRs) of SI were slightly higher with adalimumab and infliximab compared with etanercept. However, no clear pattern was observed when stratifying by line of therapy in terms of incidence rate or HR. Sensitivity analyses showed similar HRs among these treatments. Regarding TB, all 49 cases occurred during the first three lines of treatment and rarely since 2009. Conclusion The risk of serious infections does not appear to be influenced by the line of therapy in patients with RA. However, the risk of TB seems to be more frequent during the initial lines of treatment or prior to 2009. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Socioeconomic deprivation is associated with reduced response and lower treatment persistence with TNF inhibitors in rheumatoid arthritis.

Author

Zhao, Sizheng Steven, Rogers, Kira, Kearsley-Fleet, Lianne, Watson, Kath, Bosworth, Ailsa, Galloway, James, Verstappen, Suzanne, Plant, Darren, Group, BSRBR-RA Contributors, Barton, Anne, Hyrich, Kimme L, and Humphreys, Jenny H

Subjects
LIFESTYLES, BIOLOGICAL products, CONFIDENCE intervals, ANTI-inflammatory agents, REGRESSION analysis, SOCIOECONOMIC factors, ANTIRHEUMATIC agents, RISK assessment, SOCIAL isolation, TREATMENT effectiveness, COMPARATIVE studies, RHEUMATOID arthritis, GENOMICS, DESCRIPTIVE statistics, RESEARCH funding, BODY mass index, SMOKING, TERMINATION of treatment, PATIENT compliance, ODDS ratio, DISEASE management, PROPORTIONAL hazards models
Abstract

Objective To investigate the association between socioeconomic deprivation and outcomes following TNF inhibitor (TNFi) treatment. Methods Individuals commencing their first TNFi in the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) and Biologics in RA Genetics and Genomics Study Syndicate (BRAGGSS) cohort were included. Socioeconomic deprivation was proxied using the Index of Multiple Deprivation and categorized as 20% most deprived, middle 40% or 40% least deprived. DAS28-derived outcomes at 6 months (BSRBR-RA) and 3 months (BRAGGSS) were compared using regression models with the least deprived as referent. Risks of all-cause and cause-specific drug discontinuation were compared using Cox models in the BSRBR-RA. Additional analyses adjusted for lifestyle factors (e.g. smoking, BMI) as potential mediators. Results 16 085 individuals in the BSRBR-RA were included (mean age 56 years, 76% female), of whom 18%, 41% and 41% were in the most, middle and least deprived groups, respectively. Of 3459 included in BRAGGSS (mean age 57, 77% female), proportions were 22%, 36% and 41%, respectively. The most deprived group had 0.3-unit higher 6-month DAS28 (95% CI 0.22, 0.37) and were less likely to achieve low disease activity (odds ratio [OR] 0.76; 95% CI 0.68, 0.84) in unadjusted models. Results were similar for 3-month DAS28 (β = 0.23; 95% CI 0.11, 0.36) and low disease activity (OR 0.77; 95% CI 0.63, 0.94). The most deprived were more likely to discontinue treatment (hazard ratio 1.18; 95% CI 1.12, 1.25), driven by ineffectiveness rather than adverse events. Adjusted estimates were generally attenuated. Conclusion Socioeconomic deprivation is associated with reduced response to TNFi. Improvements in determinants of health other than lifestyle factors are needed to address socioeconomic inequities. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Etanercept originator versus etanercept biosimilar for the treatment of rheumatoid arthritis as a first biologic: results from the BSRBR-RA.

Author

Kearsley-Fleet, Lianne, Rokad, Aasiyah, Tsoi, Man-Fung, Zhao, Sizheng Steven, Lunt, Mark, Watson, Kath D, Group, BSRBR-RA Contributors, and Hyrich, Kimme L

Subjects
SCIENTIFIC observation, BIOSIMILARS, REGRESSION analysis, ANTIRHEUMATIC agents, TREATMENT effectiveness, RHEUMATOID arthritis, KAPLAN-Meier estimator, DESCRIPTIVE statistics, ETANERCEPT, LONGITUDINAL method, PROPORTIONAL hazards models
Abstract

Objectives Etanercept biosimilars show comparable efficacy to their originators among biologic-naïve patients with RA in randomized controlled trials. Nationwide guidelines have obligated prescribing of etanercept biosimilars from 2016, resulting in significant cost savings. This analysis aimed to compare the effectiveness of etanercept originator vs etanercept biosimilar amongst biologic-naïve RA patients treated in routine clinical practice in the UK. Methods Biologic-naïve RA patients starting etanercept in the British Society for Rheumatology Biologics Register in Rhematoid Arthritis (BSRBR-RA) cohort study from 2010 were included. Data collected at start of therapy includes patient demographics and disease activity. Follow-up data includes changes in disease activity and anti-rheumatic therapy. Six- and 12-month primary outcomes include DAS for 28-joints (DAS28) remission, EULAR response and minimal clinically important difference in function. Etanercept drug survival was assessed using Kaplan–Meier and Cox regression, including reasons for treatment withdrawal. Multiple imputation accounted for missing data. Propensity-decile adjustment was used to account for confounding by indication. Results A total of 1806 biologic-naïve RA patients started etanercept: 1009 originator, 797 biosimilar. At 6 and 12 months, the proportion of patients achieving DAS28 remission and EULAR response were similar between treatments. During follow-up, 19% of originator patients switched onto etanercept biosimilar. Patients were censored at time of switch. Patients on originator were no more likely to stop therapy vs biosimilar; 71% of originator and 76% of biosimilar patients remained on therapy at 1 year. Conclusions In one of the largest analyses of patients with RA, biologic-naïve RA patients treated with etanercept originator showed similar outcomes vs biosimilar using real-world data. Drug survival, and disease activity after 6 and 12 months of therapy, was similar between cohorts. [ABSTRACT FROM AUTHOR]

Published
2023
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6. Socioeconomic deprivation is associated with reduced response and lower treatment persistence with TNF inhibitors in rheumatoid arthritis

Author

Zhao, Sizheng Steven, Rogers, Kira, Kearsley-Fleet, Lianne, Watson, Kath, Bosworth, Ailsa, Galloway, James, Verstappen, Suzanne, Plant, Darren, Barton, Anne, Hyrich, Kimme L., and Humphreys, Jenny H.

Subjects
rheumatoid arthritis, Deprivation, index of multiple deprivation, treatment response, socioeconomic position
Abstract

Objective. To investigate the association between socioeconomic deprivation and outcomes following TNF inhibitor (TNFi) treatment.Methods. Individuals commencing their first TNFi in the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) and Biologics in RA Genetics and Genomics Study Syndicate (BRAGGSS) cohort were included. Socioeconomic deprivation was proxied using the Index of Multiple Deprivation and categorised as 20% most deprived, middle 40%, 40% least deprived. DAS28-derived outcomes at 6 months (BSRBR-RA) and 3 months (BRAGGSS) were compared using regression models with the least deprived as referent. Risks of all-cause and cause-specific drug discontinuation were compared using Cox models in the BSRBR-RA. Additional analyses adjusted for lifestyle factors (e.g., smoking, BMI) as potential mediators. Results. 16,085 individuals in the BSRBR-RA were included (mean age 56 years, 76% female), of whom 18%, 41% and 41% were in the most, middle and least deprived groups. Of 3459 included in BRAGGSS (mean age 57, 77% female), proportions were 22%, 36%, 41%, respectively. The most deprived group had 0.3-unit higher 6-month DAS28 (95%CI 0.22-0.37) and were less likely to achieve low disease activity (OR 0.76; 0.68-0.84) in unadjusted models. Results were similar for 3-month DAS28 (beta=0.23, 95%CI 0.11-0.36) and low disease activity (OR 0.77; 0.63-0.94). The most deprived were more likely to discontinue treatment (HR 1.18; 1.12-1.25), driven by ineffectiveness rather than adverse events. Adjusted estimates were generally attenuated.Conclusion. Socioeconomic deprivation is associated with reduced response to TNFi. Improvements in determinants of health other than lifestyle factors are needed to address socioeconomic inequities.

Published
2023

9. Risk of lymphoma in patients exposed to antitumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

Author

Mercer, Louise K, Galloway, James B, Lunt, Mark, Davies, Rebecca, Low, Audrey L S, Dixon, William G, Watson, Kath D, Symmons, Deborah P M, Hyrich, Kimme L, Maiden, Nicola, Price, Tom, Hopkinson, Neil, OʼReilly, Sheila, Hordon, Lesley, Griffiths, Ian, Porter, Duncan, Madhok, R, Hassell, Andy, Cooper, R G, Choy, Ernest, Walsh, David, Emery, Professor Paul, Knight, Susan, Bruce, Ian, Taggart, Allister, Scott, Professor David, Thompson, Paul, McCrae, Fiona, Goodfellow, Rhian, Kitas, Professor George, Jubb, Ronald, Abernethy, Rikki, Green, Sandra, Sanders, Paul, Coulson, Amanda, Harrison, Bev, Bukhari, Marwan, and Klimiuk, Peter

Published
2017
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12. Effectiveness of sequential biologic and targeted disease modifying anti-rheumatic drugs for rheumatoid arthritis.

Author

Zhao, Sizheng Steven, Kearsley-Fleet, Lianne, Bosworth, Ailsa, Watson, Kath, Group, BSRBR-RA Contributors, and Hyrich, Kimme L

Subjects
BIOTHERAPY, DRUG efficacy, RESEARCH, STATISTICS, INTERLEUKINS, SCIENTIFIC observation, CONFIDENCE intervals, IMMUNOGLOBULINS, MULTIVARIATE analysis, TOCILIZUMAB, REGRESSION analysis, INFLIXIMAB, ANTIRHEUMATIC agents, TREATMENT effectiveness, COMPARATIVE studies, JANUS kinases, RHEUMATOID arthritis, SURVIVAL analysis (Biometry), DESCRIPTIVE statistics, KAPLAN-Meier estimator, TUMOR necrosis factors, STATISTICAL sampling, DATA analysis, LOGISTIC regression analysis, DATA analysis software, ADALIMUMAB, NEUROTRANSMITTER uptake inhibitors, LONGITUDINAL method, SECONDARY analysis, PROPORTIONAL hazards models, ETANERCEPT, GOLIMUMAB
Abstract

Objectives Whether patients with RA benefit from repeated trials of biologic or targeted synthetic DMARDs (b/tsDMARDs) after three or more attempts is unknown. We aimed to describe treatment outcomes in each line of b/tsDMARD therapy. Methods Using data from the British Society for Rheumatology Biologics Register for RA from 2001 to 2020, change to a new b/tsDMARD (except biosimilar switches) was defined as a new line of therapy. Treatment outcomes were compared across lines of therapy, including DAS28 remission (≤2.6), low disease activity (LDA, ≤3.2) at 6 months and median time to drug discontinuation. Multiple imputation was used for missing data. Results A total of 22 934 individuals starting a first b/tsDMARD were included (mean age 56 years, 76% female), among whom 10 823 commenced a second-line drug, 5056 third, 2128 fourth, 767 fifth and 292 sixth. Most (71%) had sufficient data for DAS28-derived outcome analyses. TNF inhibitors were the most common first-line drug, but choice of subsequent-line drugs changed over time. Seventeen percent achieved DAS28 remission following first-line, 13% second and 8–13% with third through sixth. LDA was achieved in 29% of first-line, 23% second, 17–22% through to the sixth. Patients stayed on first-line therapy for a median of 2.6 years, ranging from 1.0–1.4 years for lines two to six. Conclusion Many patients will eventually benefit after repeated trials of b/tsDMARD. Further research to improve treatment selection are needed to prevent prolonged trial and error approaches in some patients. [ABSTRACT FROM AUTHOR]

Published
2022
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14. Risk of solid cancer in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

Author

Mercer, Louise K, Lunt, Mark, Low, Audrey L S, Dixon, William G, Watson, Kath D, Symmons, Deborah P M, Hyrich, Kimme L, Maiden, Nicola, Price, Tom, Hopkinson, Neil, OʼReilly, Sheila, Hordon, Lesley, Griffiths, Ian, Porter, Duncan, Madhok, R, Hassell, Andy, Cooper, R G, Choy, Ernest, Walsh, David, Emery, Paul, Knight, Susan, Bruce, Ian, Taggart, Allister, Scott, David, Thompson, Paul, McCrae, Fiona, Goodfellow, Rhian, Kitas, George, Jubb, Ronald, Abernethy, Rikki, Green, Sandra, Sanders, Paul, Coulson, Amanda, Harrison, Bev, Bukhari, Marwan, and Klimiuk, Peter

Published
2015
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19. Long-term persistence with rituximab in patients with rheumatoid arthritis

Author

Oldroyd, Alexander G S, Symmons, Deborah P M, Sergeant, Jamie C, Kearsley-Fleet, Lianne, Watson, Kath, Lunt, Mark, and Hyrich, Kimme L

Subjects
rheumatoid arthritis, Male, Time Factors, DMARDs (biologic), Clinical Science, Middle Aged, United Kingdom, Arthritis, Rheumatoid, Survival Rate, Treatment Outcome, biological therapies, Humans, Immunologic Factors, epidemiology, Female, Prospective Studies, Registries, pharmacology, Rituximab, Aged, Follow-Up Studies
Abstract

Objectives To investigate the long term persistence of rituximab (RTX) in a large observational RA cohort, investigate persistence of RTX when used as a first or second line biologic DMARD (bDMARD), to characterize subsequent bDMARD treatment following RTX. Methods Patients with RA starting treatment with RTX (MabThera) between 2008 and 2011 were recruited into the British Society for Rheumatology Biologics Register for RA. Duration of RTX treatment over the first 4 years after initiation was estimated via Kaplan-Meier estimates and the reason for discontinuation was ascertained. Subsequent bDMARD use following RTX discontinuation was characterised. Treatment survival in bDMARD-naïve (first line RTX use) and experienced (second line RTX use) cohorts was described. Results One thousand six hundred and twenty-nine patients were recruited (1371 bDMARD-experienced and 258 bDMARD-naïve). Sixty percent of the whole cohort remained on RTX after 4 years. Ineffectiveness (46%) and death (24%) were the most common reason for RTX discontinuation. RTX discontinuation was associated with RF negativity for the bDMARD-experienced cohort. Of those that discontinued RTX, 46% initiated treatment with another bDMARD, with tocilizumab being the most common. Conclusion This large study of patients initiating RTX treatment for severe RA found that 60% persisted with treatment after 4 years. This study also identified that RTX is tolerated well when used as a first or second line bDMARD.

Published
2018

20. Influence of anti-TNF patient warning regarding avoidance of high risk foods on rates of listeria and salmonella infections in the UK

Author

Davies, Rebecca, Dixon, William G, Watson, Kath D, Lunt, Mark, Symmons, Deborah P M, Hyrich, Kimme L, Maiden, Nicola, Price, Tom, Hopkinson, Neil, OʼReilly, Sheila, Hordon, Lesley, Griffiths, Ian, Porter, Duncan, Capell, Hilary, Hassell, Andy, Benitha, Romela, Choy, Ernest, Walsh, David, Emery, Paul, Knight, Susan, Bruce, Ian, Taggart, Allister, Scott, David, Thompson, Paul, McCrae, Fiona, Goodfellow, Rhian, Kitas, George, Jubb, Ronald, Abernethy, Rikki, Clarke, Shane, Green, Sandra, Sanders, Paul, Coulson, Amanda, Harrison, Bev, Bukhari, Marwan, and Klimiuk, Peter

Published
2013
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24. Predictors of low back pain in British schoolchildren: a population-based prospective cohort study

Author

Jones, Gareth T., Watson, Kath D., Silman, Alan J., Symmons, Deborah P.M., and Macfarlane Gary J.

Subjects
Interpersonal relations in children -- Physiological aspects
Abstract

Objective. To determine the onset of low back pain (LBP) in schoolchildren and to investigate the role of mechanical and psychosocial factors as risk factors for its onset. Methods. A prospective population-based cohort study was conducted of 1046 schoolchildren, aged 11 to 14 years at baseline, identified as being free of LBP, from 39 secondary schools in Northwest England. New onset of LBP at 1-year follow-up was measured. Results. Children who reported high levels of psychosocial difficulties were more likely to develop LBP than their peers (relative risk: 1.6; 95% confidence interval: 1.1-2.3). An excess risk was, in particular, associated with conduct problems (2.5; 1.7-3.7). Similarly, children who reported high numbers of somatic symptoms at baseline were at greater risk of developing LBP: abdominal pain (1.8; 1.1-3.0), headaches (1.6; 0.97-2.8), and sore throats (1.5; 0.8-2.6). In contrast, we have been unable to demonstrate a strong association between daily mechanical load (schoolbag weight) and the short-term risk of new-onset LBP (highest versus lowest quintile: 1.2; 0.7-2.1). Conclusions. In children who were initially free of LBP, adverse psychosocial factors and the presence of other preexisting somatic pain symptoms were predictive of future LBP, reflecting findings in adults. In contrast, there was little evidence of an increase in short-term risk associated with mechanical load across the range of weights commonly carried by children to school. Pediatrics 2003;111:822-828; low back pain, children, cause, mechanical, psychosocial, schoolbag., ABBREVIATIONS. LBP, low back pain; BMI, body mass index; SDQ, Strengths and Difficulties Questionnaire; RR, relative risk; IQR, interquartile range; CI, confidence interval. LOW back pain (LBP) is common in [...]

Published
2003

32. Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly

Author

Galloway, James B., Hyrich, Kimme L., Mercer, Louise K., Dixon, William G., Fu, Bo, Ustianowski, Andrew P., Watson, Kath D., Lunt, Mark, and Symmons, Deborah P. M.

Published
2011
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45. Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Author

Heathfield, Sarah, Parker, Ben, Zeef, Leo, Bruce, Ian, Alexander, Yvonne, Collins, Fraser, Stone, Michael, Wang, Edward, Williams, Anwen S., Wright, Helen L., Thomas, Huw B., Moots, Robert J., Edwards, Steven W., Bullock, Craig, Chapman, Victoria, Walsh, David A., Mobasheri, Ali, Kendall, David, Kelly, Sara, Bayley, Rachel, Buckley, Chris D., Young, Stephen P., Rump-Goodrich, Lisa, Middleton, Jim, Chen, Liye, Fisher, Roman, Kollnberger, Simon, Shastri, Nilabh, Kessler, Benedikt M., Bowness, Paul, Nazeer Moideen, Abdul, Evans, Laura, Osgood, Louise, Jones, Simon A., Nowell, Mari A., Mahadik, Younis, Young, Stephen, Morgan, Matthew, Gordon, Caroline, Harper, Lorraine, Giles, Joanna L., Paul Morgan, B., Harris, Claire L., Rysnik, Oliwia J., McHugh, Kirsty, Payeli, Sravan, Marroquin, Osiris, Shaw, Jacqueline, Renner, Christoph, Nayar, Saba, Cloake, Tom, Bombardieri, Michele, Pitzalis, Costantino, Buckley, Chris, Barone, Francesca, Lane, Peter, Coles, Mark, Williams, Emma L., Edwards, Christopher J., Cooper, Cyrus, Oreffo, Richard O., Dunn, Sara, Crawford, Aileen, Wilkinson, Mark, Le Maitre, Christine, Bunning, Rowena, Daniels, Jodie, Phillips, Kate L. E., Chiverton, Neil, Le Maitre, Christine L., Shaw, Jackie, Ridley, Anna, Wong-Baeza, Isabel, Keidel, Sarah, Chan, Antoni, Gullick, Nicola J., Abozaid, Hanan S., Jayaraj, David M., Evans, Hayley G., Scott, David L., Choy, Ernest H., Taams, Leonie S., Hickling, M., Golor, G., Jullion, A., Shaw, S., Kretsos, K., Bari, Syed F., Rhys-Dillon, Brian, Amos, Nicholson, Siebert, Stefan, Bunning, Rowena D., Haddock, Gail, Cross, Alison K., Kate, I., Phillips, E., Cross, Alison, Bunning, Rowena A. D., Ceeraz, Sabrina, Spencer, Jo, Choy, Ernest, Corrigall, Valerie, Crilly, Anne, Palmer, Helen, Lockhart, John, Plevin, Robin, Ferrell, William R., McInnes, Iain, Hutchinson, David, Perry, Liz, DiCicco, Maria, Humby, Frances, Kelly, Stephen, Hands, Rebecca, McInnes, Ian, Taylor, Peter, Mehta, Puja, Mitchell, Adam, Tysoe, Carolyn, Caswell, Richard, Owens, Martina, Vincent, Tonia, Hashmi, Tahir M., Price-Forbes, Alec, Sharp, Charlotte A., Murphy, Helen, Wood, Elizabeth F., Doherty, Teresa, Sheldon, Jo, Sofat, Nidhi, Goff, Iain, Platt, Philip N., Abdulkader, Rita, Clunie, Gavin, Ismajli, Mediola, Nikiphorou, Elena, Young, Adam, Tugnet, Nicola, Dixey, Josh, Banik, Snehashish, Alcorn, Desmond, Hunter, John, Win Maw, Win, Patil, Pravin, Hayes, Fiona, Main Wong, Way, Borg, Frances A., Dasgupta, Bhaskar, Malaviya, Anshuman P., Ostor, Andrew J., Chana, Jasroop K., Ahmed, Azeem A., Edmonds, Sally, Coward, Lucy, Borg, Frances, Heaney, Jonathan, Amft, Nicole, Simpson, John, Dhillon, Veena, Ayalew, Yezenash, Khattak, Fazlihakim, Gayed, Mary, Amarasena, Roshan I., McKenna, Frank, Mc Laughlin, Maeve, Baburaj, Krishnan, Fattah, Zozik, Ng, Nora, Wilson, Jo, Colaco, Bernard, Williams, Mark R., Adizie, Tochukwu, Casey, Matthew, Lip, Stefanie, Tan, Shaun, Anderson, David, Robertson, Calum, Devanny, Ian, Field, Max, Walker, David, Robinson, Sandra, Ryan, Sarah, Hassell, Andrew, Bateman, James, Allen, Maggie, Davies, David, Crouch, Carina, Walker-Bone, Karen, Gainsborough, Nicola, Lutalo, Pamela M., Davies, Ursula M., Mckew, Jennifer R., Millar, Auleen M., Wright, Stephen A., Bell, Aubrey L., Thapper, Muryum, Roussou, Thalia, Cumming, Jo, Hull, Richard G., McKeogh, John, O'Connor, Mortimer B., Hassan, Ahmed I., Bond, Ursula, Swan, Joan, Phelan, Mark J., Coady, David, Kumar, Namita, Farrow, Luke, Bukhari, Marwan, Oldroyd, Alexander G., Greenbank, Cathi, McBeth, John, Duncan, Rosie, Brown, Deborah, Horan, Michael, Pendleton, Neil, Littlewood, Alison, Cordingley, Lis, Mulvey, Matthew, Curtis, Elizabeth M., Cole, Zoe A., Crozier, Sarah R., Georgia, Ntani, Robinson, Siân M., Godfrey, Keith M., Sayer, Avan A., Inskip, Hazel M., Harvey, Nicholas C., Davies, Rebecca, Mercer, Louise, Galloway, James, Low, Audrey, Watson, Kath, Lunt, Mark, Symmons, Deborah, Hyrich, Kimme, Chitale, Sarang, Estrach, Cristina, Goodson, Nicola J., Rankin, Elizabeth, Jiang, C. Q., Cheng, K. K., Lam, T. H., Adab, Peymané, Ling, Stephanie, Humphreys, Jennifer, Ellis, Corrinne, Bunn, Diane, Verstappen, Suzanne M., Fluess, Elisa, Macfarlane, Gary J., Bond, Christine, Jones, Gareth T., Scott, Ian C., Steer, Sophia, Lewis, Cathryn M., Cope, Andrew, Mulvey, Matthew R., Lovell, Karina, Keeley, Philip, Woby, Steve, Beasley, Marcus, Viatte, Sebastien, Plant, Darren, Fu, Bo, Solymossy, Csilla, Worthington, Jane, Barton, Anne, Williams, Frances M., Osei-Bordom, Daniel-Clement, Popham, Maria, MacGregor, Alex, Spector, Tim, Little, Jayne, Herrick, Ariane, Pushpakom, S., Ennis, H., McBurney, H., Worthington, J., Newman, W., Ibrahim, Ibrahim, Morgan, Anne, Wilson, Anthony, Isaacs, John, Sanderson, Tessa, Hewlett, Sarah, Calnan, Michael, Morris, Marianne, Raza, Karim, Kumar, Kanta, Cardy, Caroline M., Pauling, John D., Jenkins, Jessica, Brown, Sue J., McHugh, Neil, Mugford, Miranda, Davies, Charlotte, Cooper, Nicola, Brooksby, Alan, Dures, Emma, Ambler, Nick, Fletcher, Debbie, Pope, Denise, Robinson, Frances, Rooke, Royston, Gorman, Claire L., Reynolds, Piero, Hakim, Alan J., Bosworth, Ailsa, Weaver, Dan, Kiely, Patrick D., Skeoch, Sarah, Jani, Meghna, Amarasena, Roshan, Rao, Chandini, Macphie, Elizabeth, McLoughlin, Yokemei, Shah, Preeti, Else, Sara, Semenova, Olga, Thompson, Helen, Ogunbambi, Olabambo, Kallankara, Sathish, Patel, Yusuf, Baguley, Elaine, Halsey, John, Severn, Andrew, Selvan, Shilpa, Price, Elizabeth, Husain, Muhammad J., Brophy, Sinead, Phillips, Ceri J., Cooksey, Roxanne, Irvine, Elizabeth, Lendrem, Dennis, Mitchell, Sheryl, Bowman, Simon, Pease, Colin T., Emery, Paul, Andrews, Jacqueline, Sutcliffe, Nurhan, Lanyon, Peter, Gupta, Monica, McLaren, John, Regan, Marian, Cooper, Annie, Giles, Ian, Isenberg, David, Griffiths, Bridget, Foggo, Heather, Edgar, Suzanne, Vadivelu, Saravanan, Ng, Wan-Fai, Iqbal, Itrat, Heron, Louise, Pilling, Claire, Marks, Jonathan, Hull, Richard, Ledingham, Jo, Han, Chenglong, Gathany, Tim, Tandon, Neeta, Hsia, Elizabeth, Taylor, P., Strand, V., Sensky, T., Harta, N., Fleming, S., Kay, Lesley, Rutherford, Michelle, Nicholl, Karl, Eyre, Tracey, Wilson, Gillian, Johnson, Phil, Russell, M., Timoshanko, J., Duncan, G., Spandley, A., Roskell, S., West, Louise, Adshead, Rebecca, Donnelly, Simon P., Ashton, Simon, Tahir, Hasan, Patel, Dipti, Darroch, James, Boulton, John, Ellis, Benjamin, Finlay, Ron, Murray-Brown, William, Priori, R., Tappuni, T., Vartoukian, S., Seoudi, N., Picarelli, G., Fortune, F., Valesini, G., Pitzalis, C., Bombardieri, M., Ball, Elisabeth, Rooney, Madeleine, Bell, Aubrey, Mérida, Angeles Acosta, Tarelli, Edward, Axford, John, Pericleous, Charis, Pierangeli, Silvia S., Ioannou, John, Rahman, Anisur, Alavi, Azita, Hughes, Michael, Evans, Bronwen, Zaki, Awal, Hui, Michelle, Garner, Rozeena, Rees, Frances, Bavakunji, Riaz, Daniel, Priya, Varughese, Sneha, Srikanth, Asha, Andres, Mariano, Pearce, Fiona, Leung, Jansen, Lim, Ken, Oomatia, Amin, Petri, Michelle, Fang, Hong, Birnbaum, Julius, Amissah-Arthur, Maame, Stewart, Kirsty, Jennens, Hannah, Braude, Simon, Sutton, Emily J., Watson, Kath D., Yee, Chee-Seng, Jayne, David, Akil, Mohammed, Ahmad, Yasmeen, D'Cruz, David, Khamashta, Munther, Teh, Lee-Suan, Zoma, Asad, Dey, Ida D., Kenu, Ernest, Garza-Garcia, Acely, Murfitt, Lucy, Driscoll, Paul C., Pierangeli, Silvia, Ioannou, Yiannis, Reynolds, John A., Ray, David W., O'Neill, Terence, Segeda, Iuliia, Shevchuk, Sergii, Kuvikova, Inna, Brown, Nina, Venning, Michael, Dhanjal, Mandish, Mason, Justin, Nelson-Piercy, Catherine, Basu, Neil, Paudyal, Priya, Stockton, Marie, Lawton, Sally, Dent, Caroline, Kindness, Kathy, Meldrum, Gillian, John, Elizabeth, Arthur, Catherine, West, Lucy, Macfarlane, Matthew V., Reid, David M., Yates, Max, Loke, Yoon, Watts, Richard, Christidis, Dimitrios, Williams, Mark, Sivakumar, Rajappa, Misra, Ramnath, Danda, Debashish, Mahendranath, K. M., Bacon, Paul A., and Mackie, Sarah L.

Abstract

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q < 0.00005). This was supported by qPCR analysis at 6 hrs (E-selectin and VCAM-1; 208.5 fold and 40.5, respectively above control) and also at 1, 3 and 24 hrs (E-selectin; 25.6, 93.5, 12.7 fold, respectively) (VCAM-1; 4.7, 47.2, 17.6 fold) (n = 3; p < 0.05). In contrast, HAoECs treated with TNF in combination with CZP exhibited control levels of E-selectin and VCAM-1 transcript (p > 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interest

Published
2017

46. Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Author

Mehta, Puja, Holder, Susan, Fisher, Benjamin, Vincent, Tonia, Nadesalingam, Kavitha, Maciver, Helen, Shingler, Wendy, Bakshi, Jyoti, Hassan, Sadon, D'Cruz, David, Chan, Antoni, Litwic, Anna E., McCrae, Fiona, Seth, Rakhi, Nandagudi, Anupama, Jury, Elizabeth, Isenberg, David, Karjigi, Uma, Paul, Anupam, Rees, Frances, O'Dowd, Emma, Kinnear, William, Johnson, Simon, Lanyon, Peter, Stevens, Richard, Narayan, Nehal, Marguerie, Christopher, Robinson, Helena, Ffolkes, Lorrette, Worsnop, Fiona, Ostlere, Lucy, Kiely, Patrick, Dharmapalaiah, Chethana, Hassan, Nada, Bharadwaj, Anurag, Skibinska, Malgorzata, Gendi, Nagui, Davies, Emma J., Akil, Mohammed, Kilding, Rachael, Ramachandran Nair, Jagdish, Walsh, Maeve, Farrar, Wendy, Thompson, Robert N., Borukhson, Liubov, McFadyen, Charles, Singh, Deepwant, Rajagopal, Vivek, Chan, Angela Marie L., Wearn Koh, Li, Christie, Jennifer D., Croot, Lorraine, Gayed, Mary, Disney, Benjamin, Singhal, Saket, Grindulis, Karl, Reynolds, Timothy D., Conway, Katie, Williams, Debbie, Quin, John, Dean, Gillian, Churchill, Duncan, Walker-Bone, Karen E., Goff, Iain, Reynolds, Gary, Grove, Matthew, Patel, Priya, Lazarus, Mark N., Roncaroli, Frederico, Gabriel, Carolyn, Kinderlerer, Anne R., Nikiphorou, Elena, Hall, Frances C., Bruce, Ellen, Gray, Leanne, Krutikov, Maria, Wig, Surabhi, Bruce, Ian, D'Agostino, Maria A., Wakefield, Richard, Berner Hammer, Hilde, Vittecoq, Olivier, Galeazzi, Mauro, Balint, Peter, Filippucci, Emilio, Moller, Ingrid, Iagnocco, Annamaria, Naredo, Esperanza, Ostergaard, Mikkel, Gaillez, Corine, Kerselaers, Wendy, Van Holder, Karina, Le Bars, Manuela, Stone, Millicent A., Williams, Francis, Wolber, Lisa, Karppinen, Jaro, Maatta, Juhani, Thompson, Ben, Atchia, Ismael, Lorenzi, Alice, Raftery, Graham, Platt, Phil, Platt, Philip N., Pratt, Arthur, Turmezei, Thomas D., Treece, Graham M., Gee, Andrew H., Poole, Kenneth E., Chandratre, Priyanka N., Roddy, Edward, Clarson, Lorna, Richardson, Jane, Hider, Samantha, Mallen, Christian, Lieberman, Abigail, Prouse, Peter J., Mahendran, Prini, Samarawickrama, Amanda, Ottery, Faith D., Yood, Robert, Wolfson, Marsha, Ang, Andrea, Riches, Philip, Thomson, Janet, Nuki, George, Humphreys, Jennifer, Verstappen, Suzanne M., Chipping, Jacqueline, Hyrich, Kimme, Marshall, Tarnya, Symmons, Deborah P., Roy, Matthew, Kirwan, John R., Marshall, Robert W., Matcham, Faith, Scott, Ian C., Rayner, Lauren, Hotopf, Matthew, Kingsley, Gabrielle H., Scott, David L., Steer, Sophia, Ma, Margaret H., Dahanayake, Chanaka, Kingsley, Gabrielle, Cope, Andrew, Wernham, Aaron, Ward, Lorna, Carruthers, David, Deeming, Alison, Buckley, Christopher, Raza, Karim, De Pablo, Paola, Carpenter, Lewis, Jayakumar, Keeranur, Solymossy, Csilla, Dixey, Josh, Young, Adam, Singh, Animesh, Penn, Henry, Ellerby, Nicholas, Mattey, Derek L., Packham, Jonathan, Dawes, Peter, Hider, Samantha L., Ng, Nora, Humby, Frances, Bombardieri, Michele, Kelly, Stephen, Di Cicco, Maria, Dadoun, Sabrina, Hands, Rebecca, Rocher, Vidalba, Kidd, Bruce, Pyne, Dev, Pitzalis, Costantino, Poore, Sophie, Hutchinson, David, Low, Audrey, Lunt, Mark, Mercer, Louise, Galloway, James, Davies, Rebecca, Watson, Kath, Dixon, Will, Symmons, Deborah, Watson, Kath D., Dixon, William G., Hyrich, Kimme L., Malik, Saadia P., Kelly, Clive, Hamilton, Jennifer, Heycock, Carol, Saravanan, Vadivelu, Rynne, Martin, Harris, Helen E., Tweedie, Fiona, Skaparis, Yiannis, White, Marie, Scott, Nicola, Samson, Kay, Mercieca, Cecilia, Clarke, Shane, Warner, Alexander J., Verstappen, Suzanne, Chan, Esther, Woodhead, Felix A., Nisar, Mohamed, Arthanari, S., Dawson, Julie, Sathi, Nav, Ahmad, Yasmeen, Koduri, Gouri, Cumming, Jo, Stannett, Peter, Hull, Richard, Metsios, George, Stavropoulos Kalinoglou, Antonios, Veldhuijzen van Zanten, Jet J., Nightingale, Peter, Koutedakis, Yiannis, Kitas, George D., Williams, Peter, Walsh, David, Perry, Elizabeth, de-Soyza, Anthony, Moullaali, Thomas, Eggleton, Paul, Stavropoulos-Kalinoglou, Antonios, Sandoo, Aamer, de Pablo, Paola, Maggs, Fiona, Faizal, Abdul, Pugh, Mark, Jobanputra, Paresh, Kehoe, Oksana, Cartwright, Alison, Askari, Ayman, El Haj, Alicia, Middleton, Jim, Aynsley, Sarah, Hardy, Jacob, Veale, Douglas, Fearon, Ursula, Wilson, Gerry, Muthana, Munitta, Fossati, G., Healy, L., Nesbitt, A., Becerra, Elena, Leandro, Maria J., De La Torre, Inmaculada, Cambridge, Geraldine, Nelson, P. N., Roden, D., Shaw, M., Davari Ejtehadi, Hora, Nevill, A., Freimanis, G., Hooley, P., Bowman, S., Alavi, A., Axford, J., Veitch, A. M., Tugnet, N., Rylance, P. B., Hawtree, Sarah, Mark Wilkinson, J., Wilson, Anthony G., Woon Kam, Ngar, Filter, Andrew, Croft, Adam P., Naylor, Amy, Zimmermann, Birgit, Hardie, Debbie, Desanti, Guillaume, Jaurez, Maria, Muller-Ladner, Ulf, Filer, Andrew, Neumann, Elena, Movahedi, Mohammad, Ray, David W., Burmester, Gerd R., Matucci-Cerinic, Marco, Navarro-Blasco, Francisco, Kary, Sonja, Unnebrink, Kristina, Kupper, Hartmut, Mukherjee, Sandeep, Cornell, Patricia, Richards, Selwyn, Rahmeh, Fouz, Thompson, Paul W., Westlake, Sarah L., Javaid, Muhammad K., Batra, Rajbir, Chana, Jasroop, Round, Gemma, Judge, Andrew, Taylor, Peter, Patel, Sanjeev, Cooper, Cyrus, Ravindran, Vinod, Bingham, Clifton O., Weinblatt, Michael E., Mendelsohn, Alan, Kim, Lilianne, Mack, Michael, Lu, Jiandong, Baker, Daniel, Westhovens, Rene, Hewitt, Jamie, Han, Chenglong, Keystone, Edward C., Fleischmann, Roy, Smolen, Josef, Emery, Paul, Genovese, Mark, Doyle, Mittie, Hsia, Elizabeth C., Hart, Jennifer C., Harland, Dave, Gibbons, Carl, Pang, Hok, Huertas, Catherine, Diamantopoulos, Alex, Dejonckheere, Fred, Clowse, M., Wolf, D., Stach, C., Kosutic, G., Williams, S., Terpstra, I., Mahadevan, U., Ferraccioli, G., Samborski, W., Berenbaum, F., Davies, O., Koetse, W., Bennett, B., Burkhardt, H., Luijtens, K., van der Heijde, Desiree, Mariette, X., van Vollenhoven, Ronald F., Bykerk, V., de Longueville, M., Arendt, C., Cush, J., Khan, Afsha, Maclaren, Zoe, Dubash, Sayam, Chalam, Venkat C., Sheeran, Tom, Price, Tom, Baskar, Sangeetha, Mulherin, Diarmuid, Molloy, Cauline, Keay, Fiona, Heritage, Caroline, Douglas, Barbara, Schiff, Michael H., Khanna, Dinesh, Furst, Daniel E., Maldonado, Michael A., Li, Wanying, Sasso, Eric H., Emerling, Daniel, Cavet, Guy, Ford, Kerri, Mackenzie-Green, Bronwen, Collins, David, Price, Elizabeth, Williamson, Lyn, Golla, Janardhana, Vagadia, Vipul, Morrison, Elaine, Tierney, Ann, Wilson, Hilary, Hunter, John, Reddy, Venkat, Moore, Samantha, Ehrenstein, Michael, Benson, Claire, Wray, Maria, Cairns, Andrew, Wright, Gary, Pendleton, Adrian, McHenry, Michelle, Taggart, Allister, Bell, Aubrey, Bosworth, Ailsa, Cox, Maureen, Johnston, Graeme, Shah, Preeti, O'Brien, Anne, Jones, Peter, Sargeant, Ify, Bukhari, Marwan, Nusslein, Hubert, Alten, Rieke, Lorenz, Hannes M., Boumpas, Dimitrios, Nurmohamed, Michael T., Bensen, William, Peter, Hans-Hartmut, Rainer, Franz, Pavelka, Karel, Chartier, Melanie, Poncet, Coralie, Rauch, Christiane, Lempp, Heidi, Hofmann, Darija, Adu, Aderonke, Congreve, Carron, Dobson, Joanne, Rose, Diana, Simpson, Carol, Wykes, Til, Ibrahim, Fowzia, Schiff, Michael, Nash, Peter, Durez, Patrick, Kaine, Jeffrey, Delaet, Ingrid, Kelly, Sheila, Maldonado, Michael, Patel, Salil, Jones, Graeme, Sebba, Anthony, Lepley, Denise, Devenport, Jenny, Bernasconi, Corrado, Smart, Devi, Mpofu, Chiedzo, Gomez-Reino, Juan J., Verma, Inderjeet, Kaur, Jaspreet, Syngle, Ashit, Krishan, Pawan, Vohra, Kanchan, Kaur, Ladbans, Garg, Nidhi, Chhabara, Monica, Gibson, Kellie, Woodburn, James, Telfer, Scott, Buckley, Felicity, Finckh, Axel, Huizinga, Tom W., Jansen, Jeroen P., Rubbert-Roth, Andrea, Scali, Juan J., Kremer, Joel M., Pitts, Laura, Vernon, Emma, Sharif, Mohammed I., Das, Sudipto, Helliwell, Philip, Sokoll, Katharina, and Vital, Edward M.

Subjects
cardiovascular system
Abstract

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interest

Published
2017

47. Serious infection risk after 1 year between patients with rheumatoid arthritis treated with rituximab or with a second TNFi after initial TNFi failure

Author

BSRBR-RA Contributors Group, Silva-Fernández, Lucía, De Cock, Diederik, Lunt, Mark, Low, Audrey S, Watson, Kath D, Symmons, Deborah P M, Hyrich, Kimme L, and Public Health Sciences

Subjects
Male, Time Factors, Tumor Necrosis Factor-alpha/antagonists & inhibitors, United Kingdom/epidemiology, Antirheumatic Agents/therapeutic use, Middle Aged, Treatment Outcome, Rheumatology, Arthritis, Rheumatoid/drug therapy, Rituximab/therapeutic use, Humans, Female, Morbidity/trends, Prospective Studies, Registries, Societies, Medical, Follow-Up Studies
Abstract

Objectives: Both TNF inhibitors (TNFi) and rituximab (RTX), a B-cell depleting biologic, can disrupt the immune system in RA. RTX is licensed in Europe for use following TNFi failure. However, safety data on serious infections (SIs) are scarce for RTX in daily practice. This analysis aims to compare the risk of SIs in the first year after a switch to either TNFi or RTX in patients who have failed a first TNFi. Methods: This study included patients with RA registered with the British Society for Rheumatology Biologics Register (BSRBR-RA) who switched to either a second TNFi or RTX after failing a first TNFi. Patients were followed until first SI, treatment discontinuation, last recorded follow-up or the end of the first year after the switch, whichever came first. SI was defined as requiring hospitalization, intravenous antibiotics or resulting in death. The risk of first SI was compared between TNFi and RTX using Cox proportional hazard models adjusted using propensity scores using inverse probability of treatment weighting. Results: This analysis included 3419 TNFi and 1396 RTX patients contributing 2765 and 1224 person-years (pyrs), respectively. SI occurred in 164 (4.8%) TNFi and 81 (5.8%) RTX patients giving a crude rate of 59 and 66 SI/1000 pyrs, respectively. The adjusted hazard ratio for SI was 1.0 (95% CI: 0.7, 1.4). Conclusion: The risk of SIs was comparable over the first year of treatment between TNFi and RTX treatment in patients who had failed a single prior TNFi.

Published
2018

48. Long-term Persistence with Rituximab in Patients with Rheumatoid Arthritis

Author

Oldroyd, Alexander, Symmons, Deborah, Sergeant, Jamie, Kearsley-Fleet, Lianne, Watson, Kath, Lunt, Mark, and Hyrich, Kimme

Subjects
biological therapies, Rheumatoid Arthritis, epidemiology, DMARDs (biologic), pharmacology
Abstract

ObjectivesTo investigate (i) the long term persistence of rituximab (RTX) in a large observational rheumatoid arthritis (RA) cohort, (ii) investigate persistence of RTX when used as a first or second line biologic-disease modifying anti-rheumatic drug (bDMARD) (iii) to characterise subsequent bDMARD treatment following RTX.MethodsPatients with RA starting treatment with RTX (MabThera) between 2008 and 2011 were recruited into the British Society for Rheumatology Biologics Register for RA (BSRBR-RA). Duration of RTX treatment over the first four years after initiation was estimated via Kaplan-Meier estimates and the reason for discontinuation was ascertained. Subsequent bDMARD use following RTX discontinuation was characterised. Treatment survival in bDMARD-naïve (first line RTX use) and experienced (second line RTX use) cohorts was described.Results1,629 patients were recruited (1,371 bDMARD-experienced and 258 bDMARD-naïve). Sixty percent of the whole cohort remained on RTX after four years. Ineffectiveness (46%) and death (24%) were the most common reason for RTX discontinuation. RTX discontinuation was associated with rheumatoid factor negativity for the bDMARD-experienced cohort. Of those that discontinued RTX, 46% initiated treatment with another bDMARD, with tocilizumab being the most common. ConclusionsThis large study of patients initiating RTX treatment for severe RA found that 60% persisted with treatment after four years. This study also identified that RTX is tolerated well when used as a first or second line bDMARD.

Published
2018

49. Serious infection risk after 1 year between patients with rheumatoid arthritis treated with rituximab or with a second TNFi after initial TNFi failure:results from The British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

Author

Silva-Fernandez, Lucia, Decock, Diederik, Lunt, Mark, Low, Audrey, Watson, Kath, Symmons, Deborah, and Hyrich, Kimme

Subjects
TNF inhibitors, Serious infections, Second line biological treatment, Rituximab, Observational cohort, Safety of biologicals
Abstract

BACKGROUND: Both tumour necrosis factor inhibitors (TNFi) and rituximab (RTX), a B-cell depleting biologic, can disrupt the immune system in rheumatoid arthritis (RA). RTX is licensed in Europe for use following TNFi failure. However, safety data on serious infections are scarce for RTX in daily practice. This analysis aims to compare the risk of serious infections in the first year after a switch to either TNFi or RTX in patients who have failed a first TNFiMETHODS: This study included patients with RA registered with the British Society for Rheumatology Biologics Register (BSRBR-RA) who switched to either a second TNFi or RTX after failing a first TNFi. Patients were followed until first serious infection (SI), treatment discontinuation, last recorded follow-up or the end of the first year after the switch, which ever came first. SI was defined as requiring hospitalisation, intravenous antibiotics, or resulting in death. The risk of first serious infection was compared between TNFi and RTX using Cox proportional hazard models adjusted using propensity scores using inverse probability of treatment weighting.RESULTS: This analysis included 3,419 TNFi and 1,396 RTX patients contributing 2,765 and 1,224 person-years (pyrs) respectively. SI occurred in 164 (4.8%) TNFi and 81 (5.8%) RTX patients giving a crude rate of 59 SI/1,000pyrs and 66 SI/1000pyrs respectively. The adjusted hazard ratio for SI was 1.0(95%CI 0.7-1.4).CONCLUSION: The risk of serious infections was comparable over the first year of treatment between TNFi and RTX treatment in patients who had failed a single prior TNFi.

Published
2018

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