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16. A Multicenter, Randomized, Placebo-Controlled Trial of Atorvastatin for the Primary Prevention of Cardiovascular Events in Patients With Rheumatoid Arthritis

Author

Kitas, George D, Nightingale, Peter, Armitage, Jane, Sattar, Naveed, Belch, Jill JF, Symmons, Deborah PM, Williams, Hawys, Vasishta, Shobna, Storey, Rebecca, Bruce, Ian, Durrington, Paul, McInnes, Iain, Situnayake, Deva, Struthers, Allan, Lowe, Gordon, Fox, Keith, Haskard, Dorian, Dore, Caroline, Bosworth, Ailsa, Frenneaux, Michael, Edwards, Christopher, Emberson, Jonathan, Bax, Deborah, Cobbe, Stuart, Stott, David, Sturrock, Roger, Macfarlane, Peter, Klocke, Rainer, Pullar, Tom, Tan, Su, Knight, Susan, Rowe, Iain, Kumar, Pradeep, Goodson, Nicky, Mulherin, Diarmuid, Brzeski, Micheal, Gardiner, Philip, Walker, David, Callaghan, Rob, Allen, Margaret, McCarey, David, George, Emmanuel, Deighton, Chris, Kirkham, Bruce, Teh, Lee-Suan, Luqmani, Raashid, Chakravarty, Kuntal, Roussou, Euthalia, Nixon, Jenny, Richards, Selwyn, Scott, David, Woolf, Tony, Prouse, Peter, Packham, Jonathan, Davies, Martin, DeLord, Denise, O'Neill, Terence, Pande, Ira, Watts, Richard, Rankin, Elizabeth, Papasawas, George, Emery, Paul, Morgan, Ann, Sinha, Arvind, Dasgupta, Bhaskar, Creamer, Paul, Zoma, Asad, Walsh, David, Van-Laar, Jaap, Capps, Nigel, Cairns, Andrew, Marguerie, Christopher, Kumar, Namita, Abernethy, Rikki, Lillicrap, Mark, Ralston, Stuart, Makadsi, Raad, Hopkinson, Neil, Akil, Mohammed, Ahmad, Yasmeen, Adler, Matthew, Bukhari, Marwan, Sanders, Paul, Binymin, Khalid, Hassan, Alaa, Hughes, Rod, Irani, Mike, O'Reilly, David, Sainsbury, Paul, Richmond, Ruth, Malgorzata, Magliano, Nisar, Mohammed, McEntergart, Ann, Roy, Dipak, Marks, Jeffrey, Batley, Michael, Mahmud, Taher, McKenna, Frank, Harris, Helen, Smyth, Anita, Tunn, Eddie, Young, Adam, Baburaj, Krishnan, Thomas, Joegi, Hall, Frances, Marshall, Tarnya, Rao, Chandini, Dixey, Josh, Gendi, Nagui, Birrell, Fraser, Chelliah, Gladstone, Fishman, Daniel, Knights, Sally, Coady, David, Smith, Bill, Harrison, Beverley, Naz, Sophia, Siebert, Stefan, Chan, Anthony, Putchakayala, Kiran, Al-Ansari, Atheer, Gough, Andrew, Pyne, Dev, Patel, Yusaf, Isdale, Amanda, Harvie, John, Consortium, TRACERA, Comm, Trial Management, Comm, Trial Steering, Comm, Data Monitoring, Comm, Endpoints, and Principal, TRACERA Recruiting Ctr

Published
2019

17. A multicenter, randomized, placebo‐controlled trial of atorvastatin for the primary prevention of cardiovascular events in patients with rheumatoid arthritis

Author

Kitas, George D., Nightingale, Peter, Armitage, Jane, Sattar, Naveed, Belch, Jill J. F., Symmons, Deborah P. M., Kitas, George, Belch, Jill, Symmons, Deborah, Williams, Hawys, Vasishta, Shobna, Storey, Rebecca, Bruce, Ian, Durrington, Paul, McInnes, Iain, Situnayake, Deva, Struthers, Allan, Lowe, Gordon, Fox, Keith, Haskard, Dorian, Dore, Caroline, Bosworth, Ailsa, Frenneaux, Michael, Edwards, Christopher, Emberson, Jonathan, Bax, Deborah, Cobbe, Stuart, Stott, David, Sturrock, Roger, Macfarlane, Peter, Klocke, Rainer, Pullar, Tom, Knight, Susan, Rowe, Iain, Kumar, Pradeep, Goodson, Nicky, Mulherin, Diarmuid, Brzeski, Micheal, Gardiner, Philip, Walker, David, Callaghan, Rob, Allen, Margaret, McCarey, David, George, Emmanuel, Deighton, Chris, Kirkham, Bruce, Teh, Lee‐Suan, Luqmani, Raashid, Chakravarty, Kuntal, Nixon, Jenny, Richards, Selwyn, Scott, David, Woolf, Tony, Prouse, Peter, Packham, Jonathan, Davies, Martin, DeLord, Denise, O’Neill, Terence, Pande, Ira, Harvie, John, Watts, Richard, Rankin, Elizabeth, Papasavvas, George, Emery, Paul, Sinha, Arvind, Dasgupta, Bhaskar, Creamer, Paul, Zoma, Asad, Walsh, David, Van‐Laar, Jaap, Capps, Nigel, Cairns, Andrew, Marguerie, Christopher, Kumar, Namita, Abernethy, Rikki, Lillicrap, Mark, Ralston, Stuart, Makadsi, Raad, Hopkinson, Neil, Tan, Su, Akil, Mohammed, Ahmad, Yasmeen, Adler, Matthew, Bukhari, Marwan, Sanders, Paul, Roussou, Euthalia, Binymin, Khalid, Hassan, Alaa, Hughes, Rod, O’Reilly, David, Sainsbury, Paul, Richmond, Ruth, Malgorzata, Magliano, Nisar, Mohammed, McEntergart, Ann, Roy, Dipak, Marks, Jeffrey, Batley, Michael, McKenna, Frank, Irani, Mike, Harris, Helen, Smyth, Anita, Tunn, Eddie, Young, Adam, Thomas, Joegi, Hall, Frances, Marshall, Tarnya, Rao, Chandini, Baburaj, Krishnan, Dixey, Josh, Gendi, Nagui, Birrell, Fraser, Chelliah, Gladstone, Morgan, Ann, Fishman, Daniel, Knights, Sally, Coady, David, Smith, Bill, Harrison, Beverley, Siebert, Stefan, Chan, Anthony, Putchakayala, Kiran, Al‐Ansari, Atheer, Gough, Andrew, Naz, Sophia, Pyne, Dev, Mahmud, Taher, Patel, Yusaf, and Isdale, Amanda

Abstract

Objective:\ud \ud Rheumatoid arthritis (RA) is associated with increased cardiovascular event (CVE) risk. The impact of statins in RA is not established. We assessed whether atorvastatin is superior to placebo for the primary prevention of CVEs in RA patients.\ud Methods:\ud \ud A randomized, double‐blind, placebo‐controlled trial was designed to detect a 32% CVE risk reduction based on an estimated 1.6% per annum event rate with 80% power at P < 0.05. RA patients age >50 years or with a disease duration of >10 years who did not have clinical atherosclerosis, diabetes, or myopathy received atorvastatin 40 mg daily or matching placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or any arterial revascularization. Secondary and tertiary end points included plasma lipids and safety.\ud Results:\ud \ud A total of 3,002 patients (mean age 61 years; 74% female) were followed up for a median of 2.51 years (interquartile range [IQR] 1.90, 3.49 years) (7,827 patient‐years). The study was terminated early due to a lower than expected event rate (0.70% per annum). Of the 1,504 patients receiving atorvastatin, 24 (1.6%) experienced a primary end point, compared with 36 (2.4%) of the 1,498 receiving placebo (hazard ratio [HR] 0.66 [95% confidence interval (95% CI) 0.39, 1.11]; P = 0.115 and adjusted HR 0.60 [95% CI 0.32, 1.15]; P = 0.127). At trial end, patients receiving atorvastatin had a mean ± SD low‐density lipoprotein (LDL) cholesterol level 0.77 ± 0.04 mmoles/liter lower than those receiving placebo (P < 0.0001). C‐reactive protein level was also significantly lower in the atorvastatin group than the placebo group (median 2.59 mg/liter [IQR 0.94, 6.08] versus 3.60 mg/liter [IQR 1.47, 7.49]; P < 0.0001). CVE risk reduction per mmole/liter reduction in LDL cholesterol was 42% (95% CI −14%, 70%). The rates of adverse events in the atorvastatin group (n = 298 [19.8%]) and placebo group (n = 292 [19.5%]) were similar.\ud Conclusion:\ud \ud Atorvastatin 40 mg daily is safe and results in a significantly greater reduction of LDL cholesterol level than placebo in patients with RA. The 34% CVE risk reduction is consistent with the Cholesterol Treatment Trialists’ Collaboration meta‐analysis of statin effects in other populations.

Published
2019

22. Reductions in radiographic progression in early RA over 25-years: changing contribution from RF in 2 multi-centre UK inception cohorts

Author

Carpenter, Lewis, Norton, Sam, Nikiphorou, Elena, Jayakumar, Keeranur, McWilliams, Daniel F., Rennie, Kirsten L., Dixey, Josh, Kiely, Patrick D.W., Walsh, David A., and Young, Adam

Subjects
humanities
Abstract

Objectives: To assess 5-year progression of erosions and Joint Space Narrowing (JSN), and their associations with RF status in two large, multi-centre early-RA cohorts spanning 25-years.Methods: Radiographic joint damage was recorded using the Sharp/van der Heijde (SvdH) method in the Early RA Study (ERAS) 1986-2001, and the Early RA Network (ERAN) 2002-2013. Mixed-effects negative-binomial regression estimated changes in radiographic damage over 5-years, including erosions and JSN separately. Rheumatoid Factor (RF), along with age, sex and baseline markers of disease activity were controlled for.Results: 1,216 patients from ERAS and 446 from ERAN had radiographic data. Compared to ERAS, ERAN patients had a lower mean total SvdH score at baseline (ERAN=6.2 vs. ERAS=10.5, p

Published
2017

23. Reductions in radiographic progression in early RA over 25-years:Changing contribution from RF in 2 multi-centre UK inception cohorts

Author

Carpenter, Lewis, Norton, Sam, Nikiphorou, Elena, Jayakumar, Keeranur, McWilliams, Daniel F, Rennie, Kirsten L, Dixey, Josh, Kiely, Patrick, Walsh, David Andrew, and Young, Adam

Subjects
humanities
Abstract

OBJECTIVES: To assess 5-year progression of erosions and Joint Space Narrowing (JSN), and their associations with RF status in two large, multi-centre early-RA cohorts spanning 25-years.METHODS: Radiographic joint damage was recorded using the Sharp/van der Heijde (SvdH) method in the Early RA Study (ERAS) 1986-2001, and the Early RA Network (ERAN) 2002-2013. Mixed-effects negative-binomial regression estimated changes in radiographic damage over 5-years, including erosions and JSN separately. Rheumatoid Factor (RF), along with age, sex and baseline markers of disease activity were controlled for.RESULTS: 1,216 patients from ERAS and 446 from ERAN had radiographic data. Compared to ERAS, ERAN patients had a lower mean total SvdH score at baseline (ERAN=6.2 vs. ERAS=10.5, pCONCLUSION: Radiographic progression has significantly reduced between the two cohorts, associated with lower baseline damage and other factors, including changes in early DMARD use. The impact of RF status as a prognostic marker of clinically meaningful change in radiographic progression has markedly diminished in the context of more modern treatment. This article is protected by copyright. All rights reserved.

Published
2017

25. 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

26. 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

27. Rheumatoid arthritis - clinical aspects: 134. Predictors of Joint Damage in South Africans with Rheumatoid Arthritis

Author

Ickinger, Claudia, Musenge, Eustasius, Tikly, Mohammed, Barnes, Jonathan, Donnison, C., Scott, M., Bartholomew, Peter, Rynne, Martin, Hamilton, Jennifer, Saravanan, V., Heycock, Carol, Kelly, Clive, de la Torre, Inmaculada, Moura, Rita A., Leandro, Maria, Edwards, Jonathan, Cambridge, Geraldine, Edwards, Johnathan, Daniels, Louise E., Gullick, Nicola J., Rees, Jonathan D., Kirkham, Bruce W., Rees, Jonathan, Scott, Ian C., Johnson, Deborah, Scott, David L., Kingsley, Gabrielle, Ma, Margaret H., Cope, Andrew P., Brode, Sven, Nisar, Muhammad K., Östör, Andrew J., Oakley, Stephen P., Jones, Tim, Mistlin, Alan, Panayi, Gabriel S., El Miedany, Yasser, Palmer, Deborah, Porkodi, Ramanathan, Rajendran, Panchapakesa, Waller, Rosemary, Williamson, Lyn, Collins, David, Price, Elizabeth, Juarez, Maria J., El Gaafary, Maha, Youssef, sally, Cramp, Fiona, Hewlett, Sarah, Almeida, Celia, Kirwan, John, Choy, Ernest, Chalder, Trudie, Pollock, Jon, Christensen, Robin, Mirjafari, Hoda, Verstappen, Suzanne, Bunn, Diane, Edlin, Helena, Charlton-Menys, Valentine, Pemberton, Philip, Marshall, Tarnya, Wilson, Paddy, Lunt, Mark, Symmons, Deborah, Bruce, Ian N., Bell, Carolyn, Rowe, Ian F., Jayakumar, Keeranur, Norton, Sam J., Dixey, Josh, Williams, Peter, Young, Adam, Kurunadalingam, Hariney, Parwaiz, Iram, Kumar, Kanta, Howlett, Kath, Hands, Becki, Raza, Karim, Pitzalis, Costantino, Buckley, Chris, Kelly, Stephen, Filer, Andrew, Wheater, Gill, Hogan, Vanessa E., Onno Teng, YK, Tekstra, Janneke, Tuck, Stephen P., Lafeber, Floris P., Huizinga, Tom W., Bijlsma, Johannes W., Francis, Roger M., Datta, Harish K., van Laar, Jaap, Pratt, Arthur G., Charles, Peter J., Choudhury, Muslima, Wilson, Gill, Venables, Patrick J., Isaacs, John, Stack, Rebecca, Kwiatkowska, Brygida, Rantapaa-Dahlqvist, Solbritt, Saxne, Tore, Sidiropoulos, Prodromos, Kteniadaki, Eleni, Misirlaki, Chariklia, Mann, Herman, Vencovsky, Jiri, Ciurea, Adrian, Tamborrini, Giorgio, Kyburz, Diego, Bastian, Hans, Burmester, Gerd R., Detert, Jacqueline, Buckley, Christopher D., Sheehy, Claire, Shipman, Alexa, Stech, Irina, Mukhtyar, Chetan, Atzeni, Fabiola, Sitia, Simona, Tomasoni, Livio, Gianturco, Luigi, Ricci, Cristian, Sarzi-Puttini, Piercarlo, De Gennaro Colonna, Vito, Turiel, Maurizio, Galloway, James, Low, Audrey, Mercer, Louise K., Dixon, Will, Ustianowski, Andrew, Watson, Kath, Fisher, Benjamin, Plant, Darren, Lundberg, Karin, Barton, Anne, Venables, Patrick, Lorenzi, Alice R., and Platt, Philip N.

Abstract

Background: Rheumatoid arthritis (RA) causes progressive joint damage and functional disability. Studies on factors affecting joint damage as clinical outcome are lacking in Africa. The aim of the present study was to identify predictors of joint damage in adult South Africans with established RA. Methods: A cross-sectional study of 100 black patients with RA of >5 years were assessed for joint damage using a validated clinical method, the RA articular damage (RAAD) score. Potential predictors of joint damage that were documented included socio-demographics, smoking, body mass index (BMI), disease duration, delay in disease modifying antirheumatic drug (DMARD) initiation, global disease activity as measured by the disease activity score (DAS28), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and autoantibody status. The predictive value of variables was assessed by univariate and stepwise multivariate regression analyses. A p value

Published
2017

28. Oral abstracts 3: RA Treatment and outcomesO13. Validation of jadas in all subtypes of juvenile idiopathic arthritis in a clinical setting

Author

McErlane, Flora, Beresford, Michael W., Baildam, Eileen M., Thomson, Wendy, Hyrich, Kimme, Chieng, Alice, Davidson, Joyce, Foster, Helen E., Gardner-Medwin, Janet, Lunt, Mark, Wedderburn, Lucy, Nikiphorou, Elena, Carpenter, Lewis, Kiely, Patrick, Walsh, David, Dixey, Josh, Young, Adam, Kapoor, Sabrina R., Filer, Andrew, Fitzpatrick, Martin, Fisher, Benjamin A., Taylor, Peter C., Buckley, Christopher, McInnes, Iain, Raza, Karim, Young, Stephen P., Dougados, Maxime, Kissel, Karsten, Amital, Howard, Conaghan, Philip, Martin-Mola, Emilio, Nasonov, Evgeny, Schett, Georg, Troum, Orrin, Veldi, Tiina, Bernasconi, Corrado, Huizinga, Tom, Durez, Patrick, Genovese, Mark C., Richards, Hanno B., Supronik, Jerzy, Dokoupilova, Eva, Aelion, Jacob A., Lee, Sang-Heon, Codding, Christine E., Kellner, Herbert, Ikawa, Takashi, Hugot, Sophie, Ligozio, Gregory, Mpofu, Shephard, Kavanaugh, Arthur, Emery, Paul, Fleischmann, Roy, Van Vollenhoven, Ronald, Pavelka, Karel, Guérette, Benoît, Santra, Sourav, Redden, Laura, Kupper, Hartmut, Smolen, Josef S., Wilkie, Ross, Tajar, Abdelouahid, McBeth, John, Hooper, Lindsey S., Bowen, Catherine J., Gates, Lucy, Culliford, David, Edwards, Christopher J., Arden, Nigel K., Adams, Jo, Ryan, Sarah, Haywood, Hannah, Pain, Helen, Siddle, Heidi J., Redmond, Anthony C., Waxman, Robin, Dagg, Abigail R., Alcacer-Pitarch, Begonya, Wilkins, Richard A., Helliwell, Philip S., Norton, Sam, Williams, Richard, Halls, Serena, Law, Rebecca-Jane, Jones, Jeremy, Markland, David, Maddison, Peter, Thom, Jeanette, Parker, Ben, Urowitz, Murray B., Gladman, Dafna D., Bruce, Ian, Croca, Sara C., Pericleous, Charis, Yong, Harry, Isenberg, David, Giles, Ian, Rahman, Anisur, Ioannou, Yiannis, Warrell, Clare E., Dobarro, David, Handler, Clive, Denton, Christopher P., Schreiber, Benjamin E., Coghlan, John G., Betteridge, Zoe E., Woodhead, Felix, Bunn, Christopher, Abraham, David, Desai, Sujal, du Bois, Roland, Wells, Athol, McHugh, Neil, Abignano, Giuseppina, Aydin, Sibel, Castillo-Gallego, Conception, Woods, Daniel, Meekings, Adam, McGonagle, Dennis, Del Galdo, Francesco, Vila, Josephine, Mitchell, Sheryl, Bowman, Simon, Price, Elizabeth, Pease, Colin T., Andrews, Jacqueline, Bombardieri, Michele, Sutcliffe, Nurhan, Pitzalis, Constantino, Lanyon, Peter, Hunter, John, Gupta, Monica, McLaren, John, Regan, Marian, Cooper, Annie, Vadivelu, Saravanan, Coady, David, Griffiths, Bridget, Lendrem, Dennis, Foggo, Heather, Tarn, Jessica, Ng, Wan-Fai, Goodhead, Charlotte, Shekar, Priya, Kelly, Clive, Francis, Gail, Bailey, Ann-Marie, Thompson, Lynsey, Hamilton, Jennifer, Salisbury, Chris, Foster, Nadine E., Bishop, Annette, Coast, Jo, Franchini, Angelo, Hall, Jeanette, Hollinghurst, Sandra, Hopper, Cherida, Grove, Sean, Kaur, Surinder, Montgomery, Alan, Paskins, Zoe, Sanders, Tom, Croft, Peter R., Hassell, Andy B., Coxon, Domenica E., Frisher, Martin, Jordan, Kelvin P., Jinks, Clare, Peat, George, Monk, Helen L., Muller, Sara, Mallen, Christian, Hider, Samantha L., Roddy, Edward, and Hayward, Richard

Abstract

Background: Juvenile Arthritis Disease Activity Score (JADAS) is a 4 variable composite disease activity (DA) score for JIA (including active 10, 27 or 71 joint count (AJC), physician global (PGA), parent/child global (PGE) and ESR). The validity of JADAS for all ILAR subtypes in the routine clinical setting is unknown. We investigated the construct validity of JADAS in the clinical setting in all subtypes of JIA through application to a prospective inception cohort of UK children presenting with new onset inflammatory arthritis. Methods: JADAS 10, 27 and 71 were determined for all children in the Childhood Arthritis Prospective Study (CAPS) with complete data available at baseline. Correlation of JADAS 10, 27 and 71 with single DA markers was determined for all subtypes. All correlations were calculated using Spearman's rank statistic. Results: 262/1238 visits had sufficient data for calculation of JADAS (1028 (83%) AJC, 744 (60%) PGA, 843 (68%) PGE and 459 (37%) ESR). Median age at disease onset was 6.0 years (IQR 2.6-10.4) and 64% were female. Correlation between JADAS 10, 27 and 71 approached 1 for all subtypes. Median JADAS 71 was 5.3 (IQR 2.2-10.1) with a significant difference between median JADAS scores between subtypes (p < 0.01). Correlation of JADAS 71 with each single marker of DA was moderate to high in the total cohort (see Table 1). Overall, correlation with AJC, PGA and PGE was moderate to high and correlation with ESR, limited JC, parental pain and CHAQ was low to moderate in the individual subtypes. Correlation coefficients in the extended oligoarticular, rheumatoid factor negative and enthesitis related subtypes were interpreted with caution in view of low numbers. Conclusions: This study adds to the body of evidence supporting the construct validity of JADAS. JADAS correlates with other measures of DA in all ILAR subtypes in the routine clinical setting. Given the high frequency of missing ESR data, it would be useful to assess the validity of JADAS without inclusion of the ESR. Disclosure statement: All authors have declared no conflicts of interest. Table 1Spearman's correlation between JADAS 71 and single markers DA by ILAR subtype ILAR Subtype Systemic onset JIA Persistent oligo JIA Extended oligo JIA Rheumatoid factor neg JIA Rheumatoid factor pos JIA Enthesitis related JIA Psoriatic JIA Undifferentiated JIA Unknown subtype Total cohort Number of children 23 111 12 57 7 9 19 7 17 262 AJC 0.54 0.67 0.53 0.75 0.53 0.34 0.59 0.81 0.37 0.59 PGA 0.63 0.69 0.25 0.73 0.14 0.05 0.50 0.83 0.56 0.64 PGE 0.51 0.68 0.83 0.61 0.41 0.69 0.71 0.9 0.48 0.61 ESR 0.28 0.31 0.35 0.4 0.6 0.85 0.43 0.7 0.5 0.53 Limited 71 JC 0.29 0.51 0.23 0.37 0.14 -0.12 0.4 0.81 0.45 0.41 Parental pain 0.23 0.62 0.03 0.57 0.41 0.69 0.7 0.79 0.42 0.53 Childhood health assessment questionnaire 0.25 0.57 -0.07 0.36 -0.47 0.84 0.37 0.8 0.66 0.47

Published
2017

29. Secular changes in clinical features at presentation of rheumatoid arthritis:Increase in comorbidity but improved inflammatory states

Author

Nikiphorou, Elena, Norton, Sam, Carpenter, Lewis, Dixey, Josh, Walsh, David Andrew, Kiely, Patrick, and Young, Adam

Abstract

OBJECTIVE: To examine secular trends in demographic, clinical manifestations and comorbidity on first presentation of RA prior to DMARD treatment.METHODS: 2701 patients were recruited over 25years to two UK-based RA inception cohorts: the Early RA Study (9 centres; 1986-2001) and the Early RA Network (23 centres; 2002-2012). Trends in demographic and baseline clinical/laboratory and radiographic variables and comorbidities were estimated using mixed effects models, including random effects for recruitment centre.RESULTS: Age-at-onset increased from 53.2 to 57.7 years in 1990 and 2010 respectively (2.6 months/year; 95% CI 1.2-4.1). Gender-ratio, the proportion living in deprived areas and smoking status were unchanged (p>0.05) and there were no changes in the proportion seropositive or erosive at baseline (p>0.05). After controlling for treatment at the time of assessment, ESR reduced and haemoglobin increased over time (p0.05). The overall prevalence of comorbidity increased from 29.0% in 1990 to 50.7% in 2010, mainly due to cardiovascular and non-cardiac vascular conditions including hypertension. There was a significant increase in BMI (0.15 units/year; 95% CI 0.11-0.18), resulting in an increase in the prevalence of obesity from 13.3% in 1990 to 33.6% in 2010.CONCLUSIONS: Age-at-onset and comorbidity burden, especially obesity have increased at RA presentation over 25 years, reflecting wider demographic trends at the population level. In contrast there were no accompanying changes in disease severity assessed by composite markers of disease activity, radiographic erosions, seropositivity or HAQ at presentation. Treatment strategies in early RA should take greater account of the impact of co-morbidity on outcomes. This article is protected by copyright. All rights reserved.

Published
2017

30. Association between rheumatoid arthritis disease activity, progression of functional limitation and long term risk of orthopaedic surgery:Combined analysis of two prospective cohorts supports EULAR treat to target (T2T) DAS thresholds

Author

Nikiphorou, Elena, Norton, Sam, Young, Adam, Carpenter, Lewis, Dixey, Josh, Walsh, David Andrew, Kiely, Patrick, Davies, Paul, Hill, Lynn, Gough, Andrew, Devlin, Joe, Emery, Paul, Waterhouse, Lynn, James, David, Tate, Helen, Boys, Cathy, Williams, Peter, White, Dora, Dart, Helen, Cox, Nigel, Stafford, Sue, Winfield, John, Seymour, Annie, Williams, Richard, Blunn, Karina, McDowell, Jackie, Prouse, Peter, Andrews, Sheryl, Wilson, Deborah, Magliano, Malgorzata, Perks, Ursula, Coulson, Amanda, Hassle, Andrew, Kirwan, Michele, Leone, Francesca, Dunne, Ciaran, Hawley, Lindsey, Creamer, Paul, Taylor, Julie, Wilmott, Wendy, Knights, Sally, Rowland-Axe, Rebecca, Green, Sandra, Simmons, Dawn, David, Joel, Cox, Maureen, Bukhari, Marwan, Evans, Bronwen, Batley, Michael, Oram, Catherine, and Potter, Tanya

Subjects
Treatment, Rheumatoid Arthritis, DMARDs (biologic), Disease Activity, DMARDs (synthetic)
Abstract

Objectives To examine the association between disease activity in early rheumatoid arthritis (RA), functional limitation and long-term orthopaedic episodes.Methods Health Assessment Questionnaire (HAQ) disability scores were collected from two longitudinal early RA inception cohorts in routine care; Early Rheumatoid Arthritis Study and Early Rheumatoid Arthritis Network from 1986 to 2012. The incidence of major and intermediate orthopaedic surgical episodes over 25 years was collected from national data sets. Disease activity was categorised by mean disease activity score (DAS28) annually between years 1 and 5; remission (RDAS≤2.6), low (LDAS>2.6–3.2), low-moderate (LMDAS≥3.2–4.19), high-moderate (HMDAS 4.2–5.1) and high (HDAS>5.1).Results Data from 2045 patients were analysed. Patients in RDAS showed no HAQ progression over 5 years, whereas there was a significant relationship between rising DAS28 category and HAQ at 1 year, and the rate of HAQ progression between years 1 and 5. During 27 986 person-years follow-up, 392 intermediate and 591 major surgeries were observed. Compared with the RDAS category, there was a significantly increased cumulative incidence of intermediate surgery in HDAS (OR 2.59 CI 1.49 to 4.52) and HMDAS (OR 1.8 CI 1.05 to 3.11) categories, and for major surgery in HDAS (OR 2.48 CI 1.5 to 4.11), HMDAS (OR 2.16 CI 1.32 to 3.52) and LMDAS (OR 2.07 CI 1.28 to 3.33) categories. There was no significant difference in HAQ progression or orthopaedic episodes between RDAS and LDAS categories.Conclusions There is an association between disease activity and both poor function and long-term orthopaedic episodes. This illustrates the far from benign consequences of persistent moderate disease activity, and supports European League Against Rheumatism treat to target recommendations to secure low disease activity or remission in all patients.

Published
2016

31. Remission vs low disease activity: function, quality of life and structural outcomes in the Early Rheumatoid Arthritis Study and Network.

Author

Nikiphorou, Elena, Norton, Sam J, Carpenter, Lewis, Walsh, David A, Creamer, Paul, Dixey, Josh, Young, Adam, Kiely, Patrick D W, and ERAN, for ERAS and

Subjects
HEALTH surveys, LIFE skills, EVALUATION of medical care, QUALITY of life, QUESTIONNAIRES, RHEUMATOID arthritis, DISEASE remission, STATISTICAL models, DESCRIPTIVE statistics
Abstract

Objectives To examine associations between function, quality of life and structural outcomes in patients achieving remission vs low disease activity in early RA. Methods Demographic, clinical and radiographic variables were collected at baseline and then annually from the Early Rheumatoid Arthritis Study (ERAS) and Early Rheumatoid Arthritis Network (ERAN) inception cohorts in routine care from 1986 to 2012. Disease activity was categorized: mean DAS28 score between years 1 and 5: remission [mean remission DAS (mRDAS) <2.6] or low [mean low DAS (mLDAS) 2.6–3.2]; sustained low/remission DAS28 (sLDAS/sRDAS) at years 1 and 2; and sustained Boolean remission (sBR) at years 1 and 2. Changes in HAQ and Short Form 36 Health Survey Questionnaire [SF-36; physical (PCS) and mental (MCS) component score]) and total Sharp van der Heijde (SvdH) scores for each disease activity category were modelled using multi-level models. Covariates included year of onset, age, gender and DMARD use at first visit. Results Of 2701 patients, 562 (21%) were categorized mRDAS, 330 (12%) mLDAS, 279 (10%) sRDAS, 203 (7.5%) sLDAS and 93 (3%) sBR. Patients categorized as mRDAS had increasingly divergent improved HAQ, SF-36 PCS, MCS and total SvdH scores compared with mLDAS (P -values 0.001 to <0.0001, all time points). Patients categorized as sRDAS had better HAQ, SF-36 PCS and MCS scores (P -values 0.05 to <0.0001, all time points) and SvdH scores (P = 0.05, years 3–5) over sLDAS. sBR was associated with better HAQ, and SF-36 PCS and MCS scores over sLDAS (P -values 0.002 to <0.0001, all time points). Conclusion These findings from routine care support ACR/EULAR guidelines that remission is a preferable goal over low disease activity in early RA. [ABSTRACT FROM AUTHOR]

Published
2020
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32. The association of obesity with disease activity, functional ability and quality of life in early rheumatoid arthritis: data from the Early Rheumatoid Arthritis Study/Early Rheumatoid Arthritis Network UK prospective cohorts.

Author

Nikiphorou, Elena, Norton, Sam, Young, Adam, Dixey, Josh, Walsh, David, Helliwell, Henrietta, Kiely, Patrick, and Network, Early Rheumatoid Arthritis Study and the Early Rheumatoid Arthritis

Subjects
RHEUMATOID arthritis diagnosis, AGE factors in disease, BLOOD sedimentation, CONFIDENCE intervals, HEALTH surveys, LIFE skills, LONGITUDINAL method, MEDICAL cooperation, OBESITY, QUALITY of life, QUESTIONNAIRES, RESEARCH, SYMPTOMS, BODY mass index, DISEASE prevalence, ODDS ratio, DYADIC Adjustment Scale
Abstract

Objectives. To examine associations between BMI and disease activity, functional ability and quality of life in RA. Methods. Data from two consecutive, similarly designed UK multicentre RA inception cohorts were used: the Early RA Study (ERAS) and the Early RA Network (ERAN). Recruitment figures/median follow-up for the ERAS and ERAN were 1465/10 years (maximum 25 years), and 1236/6 years (maximum 10 years), respectively. Standard demographic and clinical variables were recorded at baseline and annually. Multilevel piecewise longitudinal models with a change point at 2 years were used with the 28-joint DAS (DAS28), ESR, HAQ and 36-item Short Form Health Survey (SF-36) physical (PCS) and mental (MCS) components as dependent variables. BMI was examined in separate models as both continuous and categorical variables (based on World Health Organization definitions) and up to 5 years from disease onset. Results. BMI data from 2386 newly diagnosed RA patients (11 348 measures) showed an increase in BMI of 0.27 U annually (95% CI 0.21, 0.33). Baseline obesity was associated with a significant reduction in the odds of achieving a low year 2 DAS28 [OR 0.52 (95% CI 0.41, 0.650)]. At year 2, HAQ and SF-36 PCS scores were significantly worse but not at year 5 in patients obese at baseline. Obesity at year 2 was associated with higher DAS28 scores at year 2, but not at year 5, and also associated with significantly higher HAQ and SF-36 PCS scores at years 2 and 5. Conclusion. Obesity prevalence is rising in early RA and associates with worse disease activity, function and health-related quality of life, with a significant negative impact on achieving a low DAS28. The data argue strongly for obesity management to become central to treatment strategies in RA. [ABSTRACT FROM AUTHOR]

Published
2018
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33. Reductions in Radiographic Progression in Early Rheumatoid Arthritis Over Twenty-Five Years: Changing Contribution From Rheumatoid Factor in Two Multicenter UK Inception Cohorts.

Author

Carpenter, Lewis, Norton, Sam, Nikiphorou, Elena, Jayakumar, Keeranur, McWilliams, Daniel F., Rennie, Kirsten L., Dixey, Josh, Kiely, Patrick, Walsh, David Andrew, Young, Adam, and Early Rheumatoid Arthritis Study and the Early Rheumatoid Arthritis Network

Subjects
ANTIRHEUMATIC agents, AUTOANTIBODIES, COMPARATIVE studies, JOINTS (Anatomy), LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, RESEARCH, RHEUMATOID arthritis, TIME, EVALUATION research, SEVERITY of illness index, DISEASE progression
Abstract

Objective: To assess the 5-year progression of erosions and joint space narrowing (JSN) and their associations with rheumatoid factor (RF) status in 2 large, multicenter, early rheumatoid arthritis cohorts, spanning 25 years.Methods: Radiographic joint damage was recorded using the Sharp/van der Heijde (SHS) method in the Early Rheumatoid Arthritis Study (ERAS), 1986-2001, and the Early Rheumatoid Arthritis Network (ERAN), 2002-2013. Mixed-effects negative binomial regression estimated changes in radiographic damage over 5 years, including erosions and JSN, separately. RF, along with age, sex, and baseline markers of disease activity were controlled for.Results: A total of 1,216 patients from ERAS and 446 from ERAN had radiographic data. Compared to ERAS, ERAN patients had a lower mean total SHS score at baseline (ERAN 6.2 versus ERAS 10.5; P < 0.001) and mean annual rate of change (ERAN 2.5 per year versus ERAS 6.9 per year; P < 0.001). Seventy-four percent of ERAS and 27% of ERAN patients progressed ≥5 units. Lower scores at baseline in ERAN were largely driven by reductions in JSN (ERAS 3.9 versus ERAN 1.2; P < 0.001), along with erosions (ERAS 1.9 versus ERAN 0.8; P < 0.001). RF was associated with greater progression in each cohort, but the absolute difference in mean annual rate of change for RF-positive patients was substantially higher for ERAS (RF positive 8.6 versus RF negative 5.1; P < 0.001), relative to ERAN (RF positive 2.0 versus RF negative 1.9; P = 0.855).Conclusion: Radiographic progression was shown to be significantly reduced between the 2 cohorts, and was associated with lower baseline damage and other factors, including changes in early disease-modifying antirheumatic drug use. The impact of RF status as a prognostic marker of clinically meaningful change in radiographic progression has markedly diminished in the context of more modern treatment. [ABSTRACT FROM AUTHOR]

Published
2017
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34. Secular Changes in Clinical Features at Presentation of Rheumatoid Arthritis: Increase in Comorbidity But Improved Inflammatory States.

Author

Nikiphorou, Elena, Norton, Sam, Carpenter, Lewis, Dixey, Josh, Andrew Walsh, David, Kiely, Patrick, Young, Adam, and EARLY RHEUMATOID ARTHRITIS STUDY and the EARLY RHEUMATOID ARTHRITIS NETWORK COHORTS

Subjects
AGE factors in disease, INFLAMMATION, LONGITUDINAL method, QUESTIONNAIRES, RHEUMATOID arthritis, COMORBIDITY
Abstract

Objective: To examine secular trends in demographics, clinical manifestations, and comorbidity on first presentation of rheumatoid arthritis (RA) prior to disease-modifying antirheumatic drug treatment.Methods: A total of 2,701 patients were recruited over 25 years to 2 UK-based RA inception cohorts: the Early Rheumatoid Arthritis Study (9 centers; 1986-2001) and the Early Rheumatoid Arthritis Network (23 centers; 2002-2012). Trends in demographic and baseline clinical/laboratory and radiographic variables and comorbidities were estimated using mixed-effects models, including random effects for recruitment center.Results: Age at onset increased from 53.2 to 57.7 years in 1990 and 2010, respectively (2.6 months/year; 95% confidence interval [95% CI] 1.2, 4.1). Sex ratio, the proportion living in deprived areas, and smoking status were unchanged (P > 0.05) and there were no changes in the proportion seropositive or erosive at baseline (P > 0.05). After controlling for treatment at the time of assessment, erythrocyte sedimentation rate decreased and hemoglobin increased over time (P > 0.05); however, the Health Assessment Questionnaire (HAQ), the Disease Activity Score (DAS), the DAS in 28 joints, and joint counts were unchanged (P > 0.05). The overall prevalence of comorbidity increased from 29.0% in 1990 to 50.7% in 2010, mainly due to cardiovascular and non-cardiac vascular conditions, including hypertension. There was a significant increase in body mass index (0.15 units/year; 95% CI 0.11, 0.18), resulting in an increase in the prevalence of obesity from 13.3% in 1990 to 33.6% in 2010.Conclusion: Age at onset and comorbidity burden, especially obesity, have increased at RA presentation over 25 years, reflecting wider demographic trends at the population level. In contrast, there were no accompanying changes in disease severity assessed by composite markers of disease activity, radiographic erosions, seropositivity, or HAQ at presentation. Treatment strategies in early RA should take greater account of the impact of comorbidity on outcomes. [ABSTRACT FROM AUTHOR]

Published
2017
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35. Association between rheumatoid arthritis disease activity, progression of functional limitation and long-term risk of orthopaedic surgery: combined analysis of two prospective cohorts supports EULAR treat to target DAS thresholds.

Author

Nikiphorou, Elena, Norton, Sam, Young, Adam, Carpenter, Lewis, Dixey, Josh, Walsh, David Andrew, Kiely, Patrick, and ERAS and ERAN

Abstract

Objectives: To examine the association between disease activity in early rheumatoid arthritis (RA), functional limitation and long-term orthopaedic episodes.Methods: Health Assessment Questionnaire (HAQ) disability scores were collected from two longitudinal early RA inception cohorts in routine care; Early Rheumatoid Arthritis Study and Early Rheumatoid Arthritis Network from 1986 to 2012. The incidence of major and intermediate orthopaedic surgical episodes over 25 years was collected from national data sets. Disease activity was categorised by mean disease activity score (DAS28) annually between years 1 and 5; remission (RDAS≤2.6), low (LDAS>2.6-3.2), low-moderate (LMDAS≥3.2-4.19), high-moderate (HMDAS 4.2-5.1) and high (HDAS>5.1).Results: Data from 2045 patients were analysed. Patients in RDAS showed no HAQ progression over 5 years, whereas there was a significant relationship between rising DAS28 category and HAQ at 1 year, and the rate of HAQ progression between years 1 and 5. During 27 986 person-years follow-up, 392 intermediate and 591 major surgeries were observed. Compared with the RDAS category, there was a significantly increased cumulative incidence of intermediate surgery in HDAS (OR 2.59 CI 1.49 to 4.52) and HMDAS (OR 1.8 CI 1.05 to 3.11) categories, and for major surgery in HDAS (OR 2.48 CI 1.5 to 4.11), HMDAS (OR 2.16 CI 1.32 to 3.52) and LMDAS (OR 2.07 CI 1.28 to 3.33) categories. There was no significant difference in HAQ progression or orthopaedic episodes between RDAS and LDAS categories.Conclusions: There is an association between disease activity and both poor function and long-term orthopaedic episodes. This illustrates the far from benign consequences of persistent moderate disease activity, and supports European League Against Rheumatism treat to target recommendations to secure low disease activity or remission in all patients. [ABSTRACT FROM AUTHOR]

Published
2016
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36. Have radiographic progression rates in early rheumatoid arthritis changed? A systematic review and meta-analysis of long-term cohorts.

Author

Carpenter, Lewis, Nikiphorou, Elena, Sharpe, Rachel, Norton, Sam, Rennie, Kirsten, Bunn, Frances, Scott, David L., Dixey, Josh, and Young, Adam

Subjects
JOINT radiography, BIOMARKERS, CONFIDENCE intervals, GENETICS, INFORMATION storage & retrieval systems, MEDICAL databases, JOINTS (Anatomy), LONGITUDINAL method, MEDLINE, META-analysis, ONLINE information services, RESEARCH funding, RHEUMATOID arthritis, SYSTEMATIC reviews, PREDICTIVE validity, DISEASE progression, DESCRIPTIVE statistics, ODDS ratio
Abstract

Objective. To evaluate, firstly, all published data on baseline and annual progression rates of radiographic damage from all longitudinal observational cohorts, and secondly, the association of standard clinical and laboratory parameters with long-term radiographic joint damage. Methods. A comprehensive search of the literature from 1975 to 2014, using PubMed, SCOPUS and Cochrane databases, identified a total of 28 studies that investigated long-term radiographic progression, and 41 studies investigating predictors of long-term radiographic progression. This was submitted and approved by PROSPERO in February 2014 (Registration Number: CRD42014007589). Results. Meta-analysis indicated an overall baseline rate of 2.02%, and a yearly increase of 1.08% of maximum damage. Stratified analysis found that baseline radiographic scores did not differ significantly between cohorts recruiting patients pre- and post-1990 (2.01% vs 2.03%; P>0.01); however, the annual rate of progression was significantly reduced in the post-1990 cohorts (0.68% vs 1.50%; P<0.05). High levels of acute phase markers, baseline radiographic damage, anti-CCP and RF positivity remain consistently predictive of long-term radiographic joint damage. Conclusion. Critical changes in treatment practices over the last three decades are likely to explain the reduction in the long-term progression of structural joint damage. Acute phase markers and presence of RF/anti-CCP are strongly associated with increased radiographic progression. [ABSTRACT FROM AUTHOR]

Published
2016
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42. Mutations in ANKH Cause Chondrocalcinosis.

Author

Pendleton, Adrian, Johnson, Michelle D., Hughes, Anne, Gurley, Kyle A., Ho, Andrew M., Doherty, Michael, Dixey, Josh, Gillet, Pierre, Loeuille, Damien, McGrath, Rodney, Reginato, Antonio, Shiang, Rita, Wright, Gary, Netter, Patrick, Williams, Charlene, and Kingsley, David M.

Subjects
*CHONDROCALCINOSIS, *GENETIC mutation, *FAMILIAL diseases, *ARTHRITIS, *ARTICULAR cartilage diseases, *GENETICS
Abstract

Chondrocalcinosis (CC) is a common cause of joint pain and arthritis that is caused by the deposition of calcium-containing crystals within articular cartilage. Although most cases are sporadic, rare familial forms have been linked to human chromosomes 8 (CCAL1) or 5p (CCAL2) (Baldwin et al. 1995; Hughes et al. 1995; Andrew et al. 1999). Here, we show that two previously described families with CCAL2 have mutations in the human homolog of the mouse progressive ankylosis gene (ANKH). One of the human mutations results in the substitution of a highly conserved amino acid residue within a predicted transmembrane segment. The other creates a new ATG start site that adds four additional residues to the ANKH protein. Both mutations segregate completely with disease status and are not found in control subjects. In addition, 1 of 95 U.K. patients with sporadic CC showed a deletion of a single codon in the ANKH gene. The same change was found in a sister who had bilateral knee replacement for osteoarthritis. Each of the three human mutations was reconstructed in a full-length ANK expression construct previously shown to regulate pyrophosphate levels in cultured cells in vitro. All three of the human mutations showed significantly more activity than a previously described nonsense mutation that causes severe hydroxyapatite mineral deposition and widespread joint ankylosis in mice. These results suggest that small sequence changes in ANKH are one cause of CC and joint disease in humans. Increased ANK activity may explain the different types of crystals commonly deposited in human CCAL2 families and mutant mice and may provide a useful pharmacological target for treating some forms of human CC. [ABSTRACT FROM AUTHOR]

Published
2002
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43. Investigation of rheumatoid arthritis genetic susceptibility markers in the early rheumatoid arthritis study further replicates the TRAF1 association with radiological damage.

Author

Viatte S, Plant D, Lunt M, Fu B, Flynn E, Parker BJ, Galloway J, Solymossy C, Worthington J, Symmons DP, Dixey JJ, Young A, and Barton A

Subjects
Aged, Arthritis, Rheumatoid diagnostic imaging, Cohort Studies, Cross-Sectional Studies, Female, Genetic Markers genetics, Genotype, Humans, Longitudinal Studies, Male, Middle Aged, Polymorphism, Single Nucleotide, Radiography, Registries, Regression Analysis, Arthritis, Rheumatoid genetics, Genetic Predisposition to Disease genetics, Severity of Illness Index, TNF Receptor-Associated Factor 1 genetics
Abstract

Objective: The TRAF1 genetic region conferring susceptibility to rheumatoid arthritis (RA) has been reported to associate with radiological damage. We aimed to test RA genetic susceptibility markers for association with a continuous measure of radiological damage over time using longitudinal modeling techniques., Methods: Sixty-seven RA susceptibility variants were genotyped in 474 patients in the Early Rheumatoid Arthritis Study (ERAS) using Sequenom MassArray technology. Correlation between genetic markers and Larsen score was assessed longitudinally using zero-inflated negative binomial regression to include repeat measurements in the same individual at different timepoints. Genetic markers associated with radiological damage in ERAS were tested using the same modeling techniques on previously published data from the Norfolk Arthritis Register (NOAR)., Results: The single marker associated longitudinally with Larsen score in ERAS (p = 0.02) and in NOAR (p = 0.04) was rs2900180 at the TRAF1 locus. Analysis of individual timepoints in ERAS showed that rs2900180 displays its effect primarily on the extent of Larsen score early in the disease course. Combined longitudinal analysis of the 2 cohorts suggests further association of several loci with Larsen score (KIF5A, PTPN22, AFF3, TAGAP) and therefore a significant accumulation of RA severity markers among RA susceptibility markers (p = 0.016)., Conclusion: The marker rs2900180 is associated with the extent of radiological damage in the ERAS cohort. This represents the second independent study correlating rs2900180 at the TRAF1 locus with radiological severity in RA. Replication in a large dataset is required to establish the role of other RA susceptibility loci in disease severity.

Published
2013
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44. A prognostic model for functional outcome in early rheumatoid arthritis.

Author

Bansback N, Young A, Brennan A, and Dixey J

Subjects
Adult, Algorithms, Arthritis, Rheumatoid rehabilitation, Female, Humans, Male, Middle Aged, Models, Biological, Nomograms, Prognosis, Recovery of Function, Severity of Illness Index, Surveys and Questionnaires, Arthritis, Rheumatoid diagnosis, Arthritis, Rheumatoid physiopathology, Health Status, Rheumatology methods
Abstract

Objective: To construct a prognostic algorithm to predict 5-year functional outcome in rheumatoid arthritis (RA), based on the Health Assessment Questionnaire (HAQ)., Methods: Data from all patients with 5-year followup (n = 985) were used from an inception cohort, the Early Rheumatoid Arthritis Study (ERAS). Possibly relevant prognostic factors considered in the initial stage of the model-building process were standard clinical, radiological, and laboratory features measured at baseline and at 1 year. Multivariate analysis was performed using logistic regression, and the predictive performance of the model was tested using measures of discrimination and calibration., Results: Bootstrap resampling identified 6 variables that consistently predicted severe functional outcome. Functional grade III/IV (odds ratio 6.7) and HAQ at 1 year (odds ratio 2.4) were the most important. Other variables included socioeconomic status, hemoglobin, and radiographic and disease activity scores. Estimates of the regression coefficients and performance were corrected for over-fitting. Reasonably large values for the c-index (0.82) and the Nagelkerke R(2) (0.39) indicate that the set of prognostic factors explains the variation in outcome to a degree that implies good prediction for individual patients., Conclusion: The algorithm identifies patients in the first year of RA who are likely to have poor function by 5 years and who could potentially benefit from aggressive drug therapy. A nomogram is produced for simple application of the model in clinical practice. While further external validation is necessary, this model could allow clinicians to target aggressive therapy earlier in a patient's disease course.

Published
2006

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