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1,073 results on '"Silverman, Earl"'

208. GG-10 Imagine SLE: international multi-site assessment of genetics and inflammation in early onset and familial systemic lupus erythematosus

Author

Lewandowski, Laura B, primary, Scott, Christiaan, additional, Gómez-Martin, Diana, additional, Silverman, Earl D, additional, Aksentijevich, Ivona, additional, Deng, Zuoming, additional, Siegel, Richard M, additional, Rider, Lisa G, additional, Hasni, Sarfaraz, additional, and Kaplan, Mariana J, additional

Published
2016
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210. CE-24 Comparison of systemic lupus erythematosus in 3 different asian ethnic groups: results from the 1000 canadian faces of lupus cohort

Author

Nguyen, Mai, primary, Fortin, Paul R, additional, Silverman, Earl, additional, Pope, Janet, additional, Chedeville, Gaelle, additional, Huber, Adam, additional, Bernatsky, Sasha, additional, Clarke, Ann, additional, Pineau, Christian, additional, Hudson, Marie, additional, Arbillaga, Hector, additional, Tucker, Lori, additional, Levy, Deborah, additional, Smith, C Douglas, additional, Hitchon, Carol, additional, Zummer, Michel, additional, and Peschken, Christine A, additional

Published
2016
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213. Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial

Author

Brunner, Hermine I., Ruperto, Nicolino, Zuber, Zbigniew, Keane, Caroline, Harari, Olivier, Kenwright, Andrew, Peng, Lu, Cuttica, Ruben, Keltsev, Vladimir, Xavier, Ricardo M., Calvo, Inmaculada, Nikishina, Irina, Rubio-Pérez, Nadina, Alexeeva, Ekaterina, Chasnyk, Vyacheslav, Horneff, Gerd, Opoka-Winiarska, Violetta, Quartier, Pierre, Silva, Clovis A., Silverman, Earl, Spindler, Alberto, Baildam, Eileen, Gámir, M. Luz, Martin, Alan, Rietschel, Christoph, Siri, Daniel, Smolewska, Elzbieta, Lovell, Daniel, Martini, Alberto, De Benedetti, Fabrizio, Sherrard, T., Johnson, A., Merritt, A., Long, W., Angioloni, Simona, Carenini, Laura, Pallotti, Chiara, Mosci, Eugenia, Garrone, Marco, Gregorini, Irene, Scala, Silvia, Villa, Luca, Silvestri, Giuseppe, Espada, Graciela, Allen, Roger, Chaitow, Jeffrey, Joos, Rik, Wouters, Carine, Knupp, Sheila, Sztajnbok, Flavio, Cabral, David, Houghton, Kristin, Roth, Johannes, Schmeling, Heinrike, Job-Deslandre, Chantal, Jorgensen, Christian, Konepaut, Isabelle, Minden, Kirsten, Weller, Frank, Gerloni, Valeria, Zulian, Francesco, Burgos-Vargas, Ruben, Salazar, Carolina Duarte, Vallejo, Eunice Solis, Calvo, Armando, Chavez, José, Zavaler, Manuel Ferrandiz, Gruenpeter, Anna, Kobusinska, Katarzyna, Sarychev, Alexey, Zholobova, Elena, Ramanan, Athimalaipet, Woo, Patricia, Gedalia, Abraham, Goodman, Steven, Kimura, Yukiko, Onel, Karen, Schikler, Kenneth, and Wouters, Carine

Subjects
Genetics and Molecular Biology (all), Male, DMARDs (biologic), Juvenile Idiopathic Arthritis, Treatment, Adolescent, Adrenal Cortex Hormones, Antibodies, Monoclonal, Humanized, Antirheumatic Agents, Arthritis, Juvenile, Bronchitis, Cellulitis, Child, Child, Preschool, Disease Progression, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Maintenance Chemotherapy, Methotrexate, Pneumonia, Receptors, Interleukin-6, Remission Induction, Treatment Outcome, Rheumatology, Immunology and Allergy, Immunology, Biochemistry, Genetics and Molecular Biology (all), Arthritis, Juvenile, Biochemistry, chemistry.chemical_compound, Monoclonal, Receptors, Medicine, skin and connective tissue diseases, Humanized, Artrite, Connective tissue disease, Rheumatoid arthritis, Combination, medicine.drug, musculoskeletal diseases, medicine.medical_specialty, General Biochemistry, Genetics and Molecular Biology, Antibodies, Tocilizumab, Drug Therapy, Internal medicine, Preschool, Imunossupressores, business.industry, Interleukin-6, Clinical and Epidemiological Research, medicine.disease, Surgery, Método duplo-cego, chemistry, business
Abstract

ObjectiveTo evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA).MethodsThis three-part, randomised, placebo-controlled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) ResultsIn part 1, 188 patients received tocilizumab (ConclusionsTocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis.Trial registration number:NCT00988221.

Published
2014

215. Worse Quality of Life, Function, and Pain in Children With Enthesitis, Irrespective of Their Juvenile Arthritis Category

Author

Rumsey, Dax G., Guzman, Jaime, Rosenberg, Alan M., Huber, Adam M., Scuccimarri, Rosie, Shiff, Natalie J., Bruns, Alessandra, Feldman, Brian M., Eurich, Dean T., Benseler, Susanne, Berard, Roberta, Boire, Gilles, Bolaria, Roxana, Cabral, David, Cameron, Bonnie, Campillo, Sarah, Chan, Mercedes, Chédeville, Gaëlle, Chetaille, Anne‐Laure, Dancey, Paul, Dorval, Jean, Duffy, Ciarán, Ellsworth, Janet, Feldman, Debbie, Gross, Katherine, Haddad, Ellie, Houghton, Kristin, Johnson, Nicole, Jurencak, Roman, Lang, Bianca, Larché, Maggie, Laxer, Ronald, LeBlanc, Claire, Levy, Deborah, Luca, Nadia, Miettunen, Paivi, Morishita, Kimberly, Oen, Kiem, Petty, Ross, Ramsey, Suzanne, Roth, Johannes, Saint‐Cyr, Claire, Schmeling, Heinrike, Schneider, Rayfel, Silverman, Earl, Spiegel, Lynn, Stringer, Elizabeth, Tse, Shirley, Tucker, Lori, Turvey, Stuart, Watanabe Duffy, Karen, and Yeung, Rae

Abstract

To estimate the impact of enthesitis on patient‐reported outcomes in children with juvenile idiopathic arthritis (JIA), irrespective of JIAcategory. Children enrolled in the Research in Arthritis in Canadian Children Emphasizing Outcomes cohort were studied. Entheseal tenderness by physician examination in 33 defined locations, Juvenile Arthritis Quality of Life Questionnaire (JAQQ), Quality of My Life (QoML) Questionnaire, Childhood Health Assessment Questionnaire (C‐HAQ), and a pain visual analog scale were completed at enrollment, every 6 months for 2 years, and then yearly up to 5 years. Analyses consisted of descriptive statistics, linear mixed models for longitudinal data, and analysis of covariance. Among 1,371 patients followed for a median of 35.3 months (interquartile range 22.1, 49.2), 214 (16%) had enthesitis, of whom 137 (64%) were classified as having enthesitis‐related arthritis. After adjusting for JIAcategory and covariates, children with enthesitis reported higher JAQQ(mean raw score 2.71 versus 2.16, adjusted difference 0.41 points; 95% confidence interval [95% CI] 0.22, 0.59), higher C‐HAQ(0.47 versus 0.31, adjusted difference 0.14 points; 95% CI0.07, 0.22), higher pain (3.01 versus 1.68, adjusted difference 0.94 points; 95% CI0.64, 1.25), and lower QoML(7.02 versus 8.23, adjusted difference –0.80 points; 95% CI–1.09, –0.51) scores than children without enthesitis. These differences persisted up to 5 years. Children with enthesitis, regardless of JIAcategory, report worse patient‐reported outcomes than those without enthesitis. Thus, enthesitis should be assessed in all children with JIA.

Published
2020
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216. Earlier use of systemic immunosuppression is associated with fewer ophthalmic surgeries in paediatric non-infectious uveitis

Author

Cheung, Crystal Sin Yi, Mireskandari, Kamiar, Ali, Asim, Silverman, Earl, and Tehrani, Nasrin

Abstract

Background/aimsThere is a paucity of large trials investigating the effect of management strategies for paediatric non-infectious uveitis on complications requiring surgery. The purpose of our study is to investigate whether earlier initiation of systemic immunosuppression in paediatric non-infectious uveitis is associated with fewer ophthalmic surgeries.MethodsA retrospective review was conducted on 48 children with non-infectious uveitis assessed in 1998–2013. Patients were divided into uveitis diagnosed before December 2008 (group 1) and after January 2009 (group 2). Duration from uveitis onset to methotrexate initiation (U-MTX) and biological addition (U-Biologic) were reviewed. Follow-up visits with topical corticosteroids >3 times daily and active uveitis (≥1+ cells) during 3.5 years were documented. The main outcome measure was the need for ≥1 ophthalmic surgery at 3.5 years.ResultsIn group 1, 69.5% of patients required ≥1 ophthalmic surgery at 3.5 years versus 26.9% in group 2 (p=0.005). U-MTX was 28.9±11.8 weeks and 14.2±10.0 weeks for groups 1 and 2 (p=0.028). U-Biologic was 134.6±46.0 weeks and 82.3±43.3 weeks for groups 1 and 2 (p=0.0016). Corticosteroid use >3 times daily was 85.9±52.7 weeks and 14.6±11.1 weeks for groups 1 and 2. Multivariate regression showed methotrexate initiation within 6 months of uveitis onset lowered the likelihood of needing ophthalmic surgery at 3.5 years (OR=6.2, 95% CI 1.2 to 33.4; p=0.033). Univariate regression demonstrated biological addition within 18 months of uveitis onset reduced the likelihood of requiring ophthalmic surgery (OR 12.57, 95% CI 1.28 to 123.48; p=0.030).ConclusionEarlier control of uveitis by addition of immunosuppressive therapy reduced the need for ophthalmic surgery.

Published
2020
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219. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

Author

UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, McVean, Gilean, Taylor, Jenny C., Martin, Hilary C., Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A. Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J., Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R., Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E., Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L., Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D., Goriely, Anne, Green, Angie, Greger, Ingo H., Grocock, Russell, Gruszczyk, Anja V., Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C., Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J., McMullin, Mary Frances, Miller, Kerry A., Murray, Lisa, Németh, Andrea H., Nesbit, M. Andrew, Nutt, David, Ormondroyd, Elizabeth, Bang Oturai, Annette, Pagnamenta, Alistair, Patel, Smita Y., Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E., Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A., Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, Van Schouwenburg, Pauline A., Schuh, Anna, Silverman, Earl, Simmons, Alison, Sorensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V., Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R. F., Uhlig, Holm H., Vyas, Paresh, Vyse, Tim, Wall, Steven A., Watkins, Hugh, Whyte, Michael P., Witty, Lorna, Wright, Ben, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, McVean, Gilean, Taylor, Jenny C., Martin, Hilary C., Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A. Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J., Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R., Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E., Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L., Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D., Goriely, Anne, Green, Angie, Greger, Ingo H., Grocock, Russell, Gruszczyk, Anja V., Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C., Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J., McMullin, Mary Frances, Miller, Kerry A., Murray, Lisa, Németh, Andrea H., Nesbit, M. Andrew, Nutt, David, Ormondroyd, Elizabeth, Bang Oturai, Annette, Pagnamenta, Alistair, Patel, Smita Y., Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E., Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A., Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, Van Schouwenburg, Pauline A., Schuh, Anna, Silverman, Earl, Simmons, Alison, Sorensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V., Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R. F., Uhlig, Holm H., Vyas, Paresh, Vyse, Tim, Wall, Steven A., Watkins, Hugh, Whyte, Michael P., Witty, Lorna, and Wright, Ben

Abstract

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Published
2015

220. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

Author

Taylor, Jenny C, Martin, Hilary C, Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J, Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R, Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E, Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L, Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D, Goriely, Anne, Green, Angie, Greger, Ingo H, Grocock, Russell, Gruszczyk, Anja V, Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C, Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J, McMullin, Mary Frances, Miller, Kerry A, Murray, Lisa, Németh, Andrea H, Nesbit, M Andrew, Nutt, David, Ormondroyd, Elizabeth, Oturai, Annette Bang, Pagnamenta, Alistair, Patel, Smita Y, Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E, Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A, Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, van Schouwenburg, Pauline A, Schuh, Anna, Silverman, Earl, Simmons, Alison, Sørensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V, Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R F, Uhlig, Holm H, Vyas, Paresh, Vyse, Tim, Wall, Steven A, Watkins, Hugh, Whyte, Michael P, Witty, Lorna, Wright, Ben, Yau, Chris, Buck, David, Humphray, Sean, Ratcliffe, Peter J, Bell, John I, Wilkie, Andrew O M, Bentley, David, Donnelly, Peter, McVean, Gilean, Taylor, Jenny C, Martin, Hilary C, Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J, Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R, Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E, Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L, Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D, Goriely, Anne, Green, Angie, Greger, Ingo H, Grocock, Russell, Gruszczyk, Anja V, Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C, Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J, McMullin, Mary Frances, Miller, Kerry A, Murray, Lisa, Németh, Andrea H, Nesbit, M Andrew, Nutt, David, Ormondroyd, Elizabeth, Oturai, Annette Bang, Pagnamenta, Alistair, Patel, Smita Y, Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E, Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A, Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, van Schouwenburg, Pauline A, Schuh, Anna, Silverman, Earl, Simmons, Alison, Sørensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V, Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R F, Uhlig, Holm H, Vyas, Paresh, Vyse, Tim, Wall, Steven A, Watkins, Hugh, Whyte, Michael P, Witty, Lorna, Wright, Ben, Yau, Chris, Buck, David, Humphray, Sean, Ratcliffe, Peter J, Bell, John I, Wilkie, Andrew O M, Bentley, David, Donnelly, Peter, and McVean, Gilean

Abstract

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Published
2015

223. Autoantibodies to Dense Fine Speckles in Pediatric Diseases and Controls

Author

Schmeling, Heinrike, primary, Mahler, Michael, additional, Levy, Deborah M., additional, Moore, Katharine, additional, Stevens, Anne M., additional, Wick, James, additional, McMillan, Jacob D., additional, Horneff, Gerd, additional, Assassi, Shervin, additional, Charles, Julio, additional, Salazar, Gloria, additional, Mayes, Maureen D., additional, Silverman, Earl D., additional, Klien-Gitelman, Marissa, additional, Lee, Tzelan, additional, Brunner, Hermine I., additional, Reed, Ann M., additional, and Fritzler, Marvin J., additional

Published
2015
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226. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

Author

Taylor, Jenny C, primary, Martin, Hilary C, additional, Lise, Stefano, additional, Broxholme, John, additional, Cazier, Jean-Baptiste, additional, Rimmer, Andy, additional, Kanapin, Alexander, additional, Lunter, Gerton, additional, Fiddy, Simon, additional, Allan, Chris, additional, Aricescu, A Radu, additional, Attar, Moustafa, additional, Babbs, Christian, additional, Becq, Jennifer, additional, Beeson, David, additional, Bento, Celeste, additional, Bignell, Patricia, additional, Blair, Edward, additional, Buckle, Veronica J, additional, Bull, Katherine, additional, Cais, Ondrej, additional, Cario, Holger, additional, Chapel, Helen, additional, Copley, Richard R, additional, Cornall, Richard, additional, Craft, Jude, additional, Dahan, Karin, additional, Davenport, Emma E, additional, Dendrou, Calliope, additional, Devuyst, Olivier, additional, Fenwick, Aimée L, additional, Flint, Jonathan, additional, Fugger, Lars, additional, Gilbert, Rodney D, additional, Goriely, Anne, additional, Green, Angie, additional, Greger, Ingo H, additional, Grocock, Russell, additional, Gruszczyk, Anja V, additional, Hastings, Robert, additional, Hatton, Edouard, additional, Higgs, Doug, additional, Hill, Adrian, additional, Holmes, Chris, additional, Howard, Malcolm, additional, Hughes, Linda, additional, Humburg, Peter, additional, Johnson, David, additional, Karpe, Fredrik, additional, Kingsbury, Zoya, additional, Kini, Usha, additional, Knight, Julian C, additional, Krohn, Jonathan, additional, Lamble, Sarah, additional, Langman, Craig, additional, Lonie, Lorne, additional, Luck, Joshua, additional, McCarthy, Davis, additional, McGowan, Simon J, additional, McMullin, Mary Frances, additional, Miller, Kerry A, additional, Murray, Lisa, additional, Németh, Andrea H, additional, Nesbit, M Andrew, additional, Nutt, David, additional, Ormondroyd, Elizabeth, additional, Oturai, Annette Bang, additional, Pagnamenta, Alistair, additional, Patel, Smita Y, additional, Percy, Melanie, additional, Petousi, Nayia, additional, Piazza, Paolo, additional, Piret, Sian E, additional, Polanco-Echeverry, Guadalupe, additional, Popitsch, Niko, additional, Powrie, Fiona, additional, Pugh, Chris, additional, Quek, Lynn, additional, Robbins, Peter A, additional, Robson, Kathryn, additional, Russo, Alexandra, additional, Sahgal, Natasha, additional, van Schouwenburg, Pauline A, additional, Schuh, Anna, additional, Silverman, Earl, additional, Simmons, Alison, additional, Sørensen, Per Soelberg, additional, Sweeney, Elizabeth, additional, Taylor, John, additional, Thakker, Rajesh V, additional, Tomlinson, Ian, additional, Trebes, Amy, additional, Twigg, Stephen R F, additional, Uhlig, Holm H, additional, Vyas, Paresh, additional, Vyse, Tim, additional, Wall, Steven A, additional, Watkins, Hugh, additional, Whyte, Michael P, additional, Witty, Lorna, additional, Wright, Ben, additional, Yau, Chris, additional, Buck, David, additional, Humphray, Sean, additional, Ratcliffe, Peter J, additional, Bell, John I, additional, Wilkie, Andrew O M, additional, Bentley, David, additional, Donnelly, Peter, additional, and McVean, Gilean, additional

Published
2015
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227. The risk and nature of flares in juvenile idiopathic arthritis: results from the ReACCh-Out cohort

Author

Guzman, Jaime, primary, Oen, Kiem, additional, Huber, Adam M, additional, Watanabe Duffy, Karen, additional, Boire, Gilles, additional, Shiff, Natalie, additional, Berard, Roberta A, additional, Levy, Deborah M, additional, Stringer, Elizabeth, additional, Scuccimarri, Rosie, additional, Morishita, Kimberly, additional, Johnson, Nicole, additional, Cabral, David A, additional, Rosenberg, Alan M, additional, Larché, Maggie, additional, Dancey, Paul, additional, Petty, Ross E, additional, Laxer, Ronald M, additional, Silverman, Earl, additional, Miettunen, Paivi, additional, Chetaille, Anne-Laure, additional, Haddad, Elie, additional, Houghton, Kristin, additional, Spiegel, Lynn, additional, Turvey, Stuart E, additional, Schmeling, Heinrike, additional, Lang, Bianca, additional, Ellsworth, Janet, additional, Ramsey, Suzanne E, additional, Bruns, Alessandra, additional, Roth, Johannes, additional, Campillo, Sarah, additional, Benseler, Susanne, additional, Chédeville, Gaëlle, additional, Schneider, Rayfel, additional, Tse, Shirley M L, additional, Bolaria, Roxana, additional, Gross, Katherine, additional, Feldman, Brian, additional, Feldman, Debbie, additional, Cameron, Bonnie, additional, Jurencak, Roman, additional, Dorval, Jean, additional, LeBlanc, Claire, additional, St. Cyr, Claire, additional, Gibbon, Michele, additional, Yeung, Rae S M, additional, Duffy, Ciarán M, additional, and Tucker, Lori B, additional

Published
2015
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228. The Ped-APS registry: The antiphospholipid syndrome in childhood

Author

Campos, Lucia M., Ozisik, Kanat, Gozdasoglu, Sevgi, Rodriguez, Vilmarie, Butani, Lavjay, Susic, Gordana, Buyukgebiz, Atilla, Falcini, Fernanda, Zulian, Francesco, Rigante, Donato, Gattorno, Marco, Kenet, Gili, Revel-Vilk, Shoshana, Mukamel, Masha, Harel, Liora, Uziel, Yosef, Barash, Judith, Padeh, Shai, Berkun, Yackov, Dressler, Frank, Pruunsild, Chris, Nielsen, Susan, Silverman, Earl D., de Oliveira, Sheila Knupp Feitosa, Saad-Magalhaes, Claudia, Silva, Clovis A., Sztajnbok, Flavio R., Garay, Stella, Meroni, Pier Luigi, Martini, Alberto, Ravelli, Angelo, Cervera, Ricard, Rozman, B., Kuzmanovska, Dafina B., Cimaz, R., and Avčin, Tadej

Subjects
Pediatrics, medicine.medical_specialty, Clinical immunology, business.industry, Antiphospholipid antibodies, Paediatrics, Thrombosis, medicine.disease, Vein thrombosis, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Rheumatology, immune system diseases, Antiphospholipid syndrome, Antiphospholipid Syndrome, Child, Humans, Registries, Phospholipid antibody, Medicine, University medical, business
Abstract

In recent years, antiphospholipid syndrome (APS) has been increasingly recognised in various paediatric autoimmune and nonautoimmune diseases, but the relatively low prevalence and heterogeneity of APS in childhood made it very difficult to study in a systematic way. The project of an international registry of paediatric patients with APS (the Ped-APS Registry) was initiated in 2004 to foster and conduct multicentre, controlled studies with large number of paediatric APS patients. The Ped-APS Registry is organised as a collaborative project of the European Forum on Antiphospholipid Antibodies and Juvenile Systemic Lupus Erythematosus Working Group of the Paediatric Rheumatology European Society. Currently, it documents a standardised clinical, laboratory and therapeutic data of 133 children with antiphospholipid antibodies (aPL)-related thrombosis from 14 countries. The priority projects for future research of the Ped-APS Registry include prospective enrolment of new patients with aPL-related thrombosis, assessment of differences between the paediatric and adult APS, evaluation of proinflammatory genotype as a risk factor for APS manifestations in childhood and evaluation of patients with isolated nonthrombotic aPL-related manifestations. © The Author(s), 2009.

Published
2009

229. Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial.

Author

Brunner, Hermine I., Ruperto, Nicolino, Tzaribachev, Nikolay, Horneff, Gerd, Chasnyk, Vyacheslav G., Panaviene, Violeta, Abud-Mendoza, Carlos, Reiff, Andreas, Alexeeva, Ekaterina, Rubio-Pérez, Nadina, Keltsev, Vladimir, Kingsbury, Daniel J., del Rocio Maldonado Velázquez, Maria, Nikishina, Irina, Silverman, Earl D., Joos, Rik, Smolewska, Elzbieta, Bandeira, Márcia, Minden, Kirsten, and van Royen-Kerkhof, Annet

Subjects
DRUG therapy for arthritis, SUBCUTANEOUS injections, ANTIRHEUMATIC agents, ARTHRITIS, COMBINATION drug therapy, COMPARATIVE studies, RESEARCH methodology, MEDICAL cooperation, METHOTREXATE, MONOCLONAL antibodies, RESEARCH, JUVENILE idiopathic arthritis, EVALUATION research, RANDOMIZED controlled trials, TREATMENT effectiveness, DISEASE remission, BLIND experiment
Abstract

Objective: This report aims to determine the safety, pharmacokinetics (PK) and efficacy of subcutaneous golimumab in active polyarticular-course juvenile idiopathic arthritis (polyJIA).Methods: In this three-part randomised double-blinded placebo-controlled withdrawal trial, all patients received open-label golimumab (30 mg/m2 of body surface area; maximum: 50 mg/dose) every 4 weeks together with weekly methotrexate during Part 1 (weeks 0-16). Patients with at least 30% improvement per American College of Rheumatology Criteria for JIA (JIA ACR30) in Part 1 entered the double-blinded Part 2 (weeks 16-48) after 1:1 randomisation to continue golimumab or start placebo. In Part 3, golimumab was continued or could be restarted as in Part 1. The primary outcome was JIA flares in Part 2; secondary outcomes included JIA ACR50/70/90 responses, clinical remission, PK and safety.Results: Among 173 patients with polyJIA enrolled, 89.0% (154/173) had a JIA ACR30 response and 79.2%/65.9%/36.4% demonstrated JIA ACR50/70/90 responses in Part 1. At week 48, the primary endpoint was not met as treatment groups had comparable JIA flare rates (golimumab vs placebo: 32/78=41% vs 36/76=47%; p=0.41), and rates of clinical remission were comparable (golimumab vs placebo: 10/78=12.8% vs 9/76=11.8%). Adverse event and serious adverse event rates were similar in the treatment groups during Part 2. Injection site reactions occurred with <1% of all injections. PK analysis confirmed adequate golimumab dosing for polyJIA.Conclusion: Although the primary endpoint was not met, golimumab resulted in rapid, clinically meaningful, improvement in children with active polyJIA. Golimumab was well tolerated, and no unexpected safety events occurred.Clinical Trial Registration: NCT01230827; Results. [ABSTRACT FROM AUTHOR]

Published
2018
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230. Prenatal exposure to antimalarials decreases the risk of cardiac but not non-cardiac neonatal lupus: a single-centre cohort study.

Author

Barsalou, Julie, Jaeggi, Edgar, Laskin, Carl A., Brown, Patrick, Tian, Simon Y., Hamilton, Robert M., and Silverman, Earl D.

Subjects
SYSTEMIC lupus erythematosus, ANTIMALARIALS, HEART block, LONGITUDINAL method, TREATMENT effectiveness, RETROSPECTIVE studies, DATA analysis software, DESCRIPTIVE statistics, ODDS ratio, MATERNAL exposure, CHILDREN, PREGNANCY, THERAPEUTICS, DISEASE risk factors
Abstract

Objective. Recent studies have suggested that prenatal exposure to HCQ reduces the risk of cardiac neonatal lupus. The aim of this study is to assess if maternal intake of antimalarials (AMs) throughout pregnancy lowered the risk of cardiac and non-cardiac neonatal lupus. Methods. Consecutive children seen between 1 January 1984 to 1 October 2013 born to women with a CTD and positive anti-Ro and/or anti-La antibodies were eligible for this single-centre retrospective cohort study. A total of 315 individuals were screened and 268 participants were included. Exposure to AMs was defined as HCQ or chloroquine throughout pregnancy. Outcomes were cardiac and non-cardiac neonatal lupus. Frequentist and Bayesian analyses were performed. We hypothesized that prenatal AM exposure would decrease the risk of cardiac but not non-cardiac neonatal lupus. Results. A total of 268 pregnancies were included; 73 were exposed to AMs throughout pregnancy. Ninety-nine children developed neonatal lupus, 117 remained unaffected and 52 children did not develop cardiac neonatal lupus but could not be categorized as unaffected since their full non-cardiac neonatal lupus status was unknown. Logistic regression suggested a protective effect of AM on cardiac neonatal lupus, but results were not statistically significant [odds ratio (OR) 0.21; P = 0.07]. Bayesian analysis showed that the probability of obtaining a protective effect (OR<1.0) for cardiac neonatal lupus was significant (98.7%). The effect of AMs on non-cardiac neonatal lupus was not significant (OR 0.78; P = 0.21). Conclusion. In this large single-centre cohort study, exposure to AMs throughout pregnancy was asso- ciated with a decreased probability of developing cardiac but not non-cardiac neonatal lupus. [ABSTRACT FROM AUTHOR]

Published
2017
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232. Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein.

Author

Ardoin, Stacy P, Ardoin, Stacy P, Schanberg, Laura Eve, Sandborg, Christy I, Barnhart, Huiman X, Evans, Greg W, Yow, Eric, Mieszkalski, Kelly L, Ilowite, Norman T, Eberhard, Anne, Imundo, Lisa F, Kimura, Yuki, Levy, Deborah, von Scheven, Emily, Silverman, Earl, Bowyer, Suzanne L, Punaro, L, Singer, Nora G, Sherry, David D, McCurdy, Deborah K, Klein-Gitelman, Marissa, Wallace, Carol, Silver, Richard M, Wagner-Weiner, Linda, Higgins, Gloria C, Brunner, Hermine I, Jung, Lawrence, Soep, Jennifer B, Reed, Ann M, Thompson, Susan D, APPLE investigators, Ardoin, Stacy P, Ardoin, Stacy P, Schanberg, Laura Eve, Sandborg, Christy I, Barnhart, Huiman X, Evans, Greg W, Yow, Eric, Mieszkalski, Kelly L, Ilowite, Norman T, Eberhard, Anne, Imundo, Lisa F, Kimura, Yuki, Levy, Deborah, von Scheven, Emily, Silverman, Earl, Bowyer, Suzanne L, Punaro, L, Singer, Nora G, Sherry, David D, McCurdy, Deborah K, Klein-Gitelman, Marissa, Wallace, Carol, Silver, Richard M, Wagner-Weiner, Linda, Higgins, Gloria C, Brunner, Hermine I, Jung, Lawrence, Soep, Jennifer B, Reed, Ann M, Thompson, Susan D, and APPLE investigators

Abstract

ObjectiveParticipants in the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) trial were randomised to placebo or atorvastatin for 36 months. The primary endpoint, reduced carotid intima medial thickness (CIMT) progression, was not met but atorvastatin-treated participants showed a trend of slower CIMT progression. Post-hoc analyses were performed to assess subgroup benefit from atorvastatin therapy.MethodsSubgroups were prespecified and defined by age (> or ≤15.5 years), systemic lupus erythematosus (SLE) duration (> or ≤24 months), pubertal status (Tanner score≥4 as post-pubertal or <4 as pre-pubertal), low density lipoprotein cholesterol (LDL) (≥ or <110 mg/dl) and high-sensitivity C reactive protein (hsCRP) (≥ or <1.5 mg/l). A combined subgroup (post-pubertal and hsCRP≥1.5 mg/l) was compared to all others. Longitudinal linear mixed-effects models were developed using 12 CIMT and other secondary APPLE outcomes (lipids, hsCRP, disease activity and damage, and quality of life). Three way interaction effects were assessed for models.ResultsSignificant interaction effects with trends of less CIMT progression in atorvastatin-treated participants were observed in pubertal (3 CIMT segments), high hsCRP (2 CIMT segments), and the combined high hsCRP and pubertal group (5 CIMT segments). No significant treatment effect trends were observed across subgroups defined by age, SLE duration, LDL for CIMT or other outcome measures.ConclusionsPubertal status and higher hsCRP were linked to lower CIMT progression in atorvastatin-treated subjects, with most consistent decreases in CIMT progression in the combined pubertal and high hsCRP group. While secondary analyses must be interpreted cautiously, results suggest further research is needed to determine whether pubertal lupus patients with high CRP benefit from statin therapy.Trial registrationClinical Trials.gov Identifier: NCT00065806.

Published
2014

238. The outcomes of juvenile idiopathic arthritis in children managed with contemporary treatments: results from the ReACCh-Out cohort

Author

Guzman, Jaime, primary, Oen, Kiem, additional, Tucker, Lori B, additional, Huber, Adam M, additional, Shiff, Natalie, additional, Boire, Gilles, additional, Scuccimarri, Rosie, additional, Berard, Roberta, additional, Tse, Shirley M L, additional, Morishita, Kimberly, additional, Stringer, Elizabeth, additional, Johnson, Nicole, additional, Levy, Deborah M, additional, Duffy, Karen Watanabe, additional, Cabral, David A, additional, Rosenberg, Alan M, additional, Larché, Maggie, additional, Dancey, Paul, additional, Petty, Ross E, additional, Laxer, Ronald M, additional, Silverman, Earl, additional, Miettunen, Paivi, additional, Chetaille, Anne-Laure, additional, Haddad, Elie, additional, Houghton, Kristin, additional, Spiegel, Lynn, additional, Turvey, Stuart E, additional, Schmeling, Heinrike, additional, Lang, Bianca, additional, Ellsworth, Janet, additional, Ramsey, Suzanne, additional, Bruns, Alessandra, additional, Campillo, Sarah, additional, Benseler, Susanne, additional, Chédeville, Gaëlle, additional, Schneider, Rayfel, additional, Yeung, Rae, additional, and Duffy, Ciarán M, additional

Published
2014
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240. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test

Author

Lionel, Anath C, Costain, Gregory, Monfared, Nasim, Walker, Susan, Reuter, Miriam S, Hosseini, S Mohsen, Thiruvahindrapuram, Bhooma, Merico, Daniele, Jobling, Rebekah, Nalpathamkalam, Thomas, Pellecchia, Giovanna, Sung, Wilson W L, Wang, Zhuozhi, Bikangaga, Peter, Boelman, Cyrus, Carter, Melissa T, Cordeiro, Dawn, Cytrynbaum, Cheryl, Dell, Sharon D, Dhir, Priya, Dowling, James J, Heon, Elise, Hewson, Stacy, Hiraki, Linda, Inbar-Feigenberg, Michal, Klatt, Regan, Kronick, Jonathan, Laxer, Ronald M, Licht, Christoph, MacDonald, Heather, Mercimek-Andrews, Saadet, Mendoza-Londono, Roberto, Piscione, Tino, Schneider, Rayfel, Schulze, Andreas, Silverman, Earl, Siriwardena, Komudi, Snead, O Carter, Sondheimer, Neal, Sutherland, Joanne, Vincent, Ajoy, Wasserman, Jonathan D, Weksberg, Rosanna, Shuman, Cheryl, Carew, Chris, Szego, Michael J, Hayeems, Robin Z, Basran, Raveen, Stavropoulos, Dimitri J, Ray, Peter N, Bowdin, Sarah, Meyn, M Stephen, Cohn, Ronald D, Scherer, Stephen W, and Marshall, Christian R

Abstract

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

Published
2018
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241. Outcome of children with fetal, neonatal or childhood diagnosis of isolated congenital atrioventricular block. A single institution's experience of 30 years

Author

Jaeggi, Edgar T, Hamilton, Robert M, Silverman, Earl D, Zamora, Samuel A, and Hornberger, Lisa K

Subjects
Fetal Diseases/ultrasonography, Male, Pacemaker, Artificial, ddc:618, Hydrops Fetalis/complications, Heart Block/diagnosis/mortality/therapy, Hydrops Fetalis, Age Factors, Survival Analysis, Fetal Diseases, Heart Block, Risk Factors, Prenatal Diagnosis, Humans, Female, Child, Ultrasonography
Abstract

ObjectivesWe reviewed our institution’s experience with isolated (congenital) third-degree atrioventricular block (CAVB) to identify pre- and post-natal predictors of mortality and the requirement for pacemakers in infancy and childhood.BackgroundBecause of the relative rarity of the disease, there is a paucity of data concerning the outcome of fetuses and children with isolated CAVB.MethodsThe medical records of all cases of CAVB encountered at our institution from January 1965 to December 1998 were analyzed.ResultsOf 102 cases identified, 29 were diagnosed in utero (F) at 26.1 ± 5.6 weeks gestation, 33 as neonates (N; ≤28 days), and 40 as children (C) at 5.7 ± 4.8 years of age. Anti-Ro and/or anti-La were present in 95% of F and 90% of N, but only in 5% of C mothers tested (p < 0.0001). Patients with CAVB having F, N and C diagnosis had a mortality of 43%, 6% and 0%, respectively, in the first two decades of life. Increased mortality risk was associated with a fetal diagnosis of CAVB (13/15 deaths; p < 0.05), fetal hydrops (6/6 cases; p < 0.0001), endocardial fibroelastosis (5/5 cases; p < 0.0001) and delivery at ≤32 weeks (4/6 cases; p < 0.05). Timing of pacemaker implantation differed significantly among F versus N (p < 0.05) and N versus C (p < 0.001) cases. At 20 years of age only 11% and 12% of CAVB patients with N and C diagnosis, respectively, were not paced.ConclusionsPre-natal diagnosis of CAVB is associated with high fetal and neonatal mortality. Among survivors, whether the diagnosis is made before or after birth, most undergo pacemaker implantation by adulthood, with earlier intervention and a significantly greater need for reintervention among those diagnosed in utero.

Published
2002

242. Cancer risk in childhood-onset systemic lupus.

Author

Schanberg, Laura, Schanberg, Laura, Silverman, Earl, Brunner, Hermine, Haines, Kathleen, Cron, Randy, ONeil, Kathleen, Oen, Kiem, Rosenberg, Alan, Duffy, Ciarán, Joseph, Lawrence, Lee, Jennifer, Kale, Mruganka, Turnbull, Elizabeth, Ramsey-Goldman, Rosalind, Bernatsky, Sasha, Clarke, Ann, Labrecque, Jeremy, Von Scheven, Emily, Schanberg, Laura, Schanberg, Laura, Silverman, Earl, Brunner, Hermine, Haines, Kathleen, Cron, Randy, ONeil, Kathleen, Oen, Kiem, Rosenberg, Alan, Duffy, Ciarán, Joseph, Lawrence, Lee, Jennifer, Kale, Mruganka, Turnbull, Elizabeth, Ramsey-Goldman, Rosalind, Bernatsky, Sasha, Clarke, Ann, Labrecque, Jeremy, and Von Scheven, Emily

Abstract

INTRODUCTION: The aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE). METHODS: We ascertained cancers within SLE registries at 10 pediatric centers. Subjects were linked to cancer registries for the observational interval, spanning 1974 to 2009. The ratio of observed to expected cancers represents the standardized incidence ratio (SIR) or relative cancer risk in childhood-onset SLE, versus the general population. RESULTS: There were 1020 patients aged <18 at cohort entry. Most (82%) were female and Caucasian; mean age at cohort entry was 12.6 years (standard deviation (SD) = 3.6). Subjects were observed for a total of 7,986 (average 7.8) patient-years. Within this interval, only three invasive cancers were expected. However, 14 invasive cancers occurred with an SIR of 4.7, 95% confidence interval (CI) 2.6 to 7.8. Three hematologic cancers were found (two non-Hodgkin’s lymphoma, one leukemia), for an SIR of 5.2 (95% CI 1.1 to 15.2). The SIRs stratified by age group and sex, were similar across these strata. There was a trend for highest cancer occurrence 10 to 19 years after SLE diagnosis. CONCLUSIONS: These results suggest an increased cancer risk in pediatric onset SLE versus the general population. In absolute terms, this represents relatively few events. Of note, risk may be highest only after patients have transferred to adult care.

Published
2013

243. Cancer risk in childhood-onset systemic lupus

Author

Bernatsky, Sasha, Bernatsky, Sasha, Clarke, Ann E, Labrecque, Jeremy, von Scheven, Emily, Schanberg, Laura E, Silverman, Earl D, Brunner, Hermine I, Haines, Kathleen A, Cron, Randy Q, O’Neil, Kathleen M, Oen, Kiem, Rosenberg, Alan M, Duffy, Ciarán M, Joseph, Lawrence, Lee, Jennifer L, Kale, Mruganka, Turnbull, Elizabeth M, Ramsey-Goldman, Rosalind, Bernatsky, Sasha, Bernatsky, Sasha, Clarke, Ann E, Labrecque, Jeremy, von Scheven, Emily, Schanberg, Laura E, Silverman, Earl D, Brunner, Hermine I, Haines, Kathleen A, Cron, Randy Q, O’Neil, Kathleen M, Oen, Kiem, Rosenberg, Alan M, Duffy, Ciarán M, Joseph, Lawrence, Lee, Jennifer L, Kale, Mruganka, Turnbull, Elizabeth M, and Ramsey-Goldman, Rosalind

Abstract

Introduction The aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE). Methods We ascertained cancers within SLE registries at 10 pediatric centers. Subjects were linked to cancer registries for the observational interval, spanning 1974 to 2009. The ratio of observed to expected cancers represents the standardized incidence ratio (SIR) or relative cancer risk in childhood-onset SLE, versus the general population. Results There were 1020 patients aged <18 at cohort entry. Most (82%) were female and Caucasian; mean age at cohort entry was 12.6 years (standard deviation (SD) = 3.6). Subjects were observed for a total of 7,986 (average 7.8) patient-years. Within this interval, only three invasive cancers were expected. However, 14 invasive cancers occurred with an SIR of 4.7, 95% confidence interval (CI) 2.6 to 7.8. Three hematologic cancers were found (two non-Hodgkin’s lymphoma, one leukemia), for an SIR of 5.2 (95% CI 1.1 to 15.2). The SIRs stratified by age group and sex, were similar across these strata. There was a trend for highest cancer occurrence 10 to 19 years after SLE diagnosis. Conclusions These results suggest an increased cancer risk in pediatric onset SLE versus the general population. In absolute terms, this represents relatively few events. Of note, risk may be highest only after patients have transferred to adult care.

Published
2013

250. High-density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups

Author

Namjou, Bahram, Sestak, Andrea L., Armstrong, Don L., Zidovetzki, Raphael, Kelly, Jennifer A., Jacob, Noam, Ciobanu, Voicu, Kaufman, Kenneth M., Ojwang, Joshua O., Ziegler, Julie, Quismorio, Francesco P., Reiff, Andreas, Myones, Barry L., Guthridge, Joel M., Nath, Swapan K., Bruner, Gail R., Mehrian-Shai, Ruth, Silverman, Earl, Klein-Gitelman, Marisa, McCurdy, Deborah, Wagner-Weiner, Linda, Nocton, James J., Putterman, Chaim, Bae, Sang-Cheol, Kim, Yun Jung, Petri, Michelle, Reveille, John D., Vyse, Timothy J., Gilkeson, Gary S., Kamen, Diane L., Alarcón-Riquelme, Marta E., Gaffney, Patrick M., Moser, Kathy L., Merrill, Joan T., Scofield, R. Hal, James, Judith A., Langefeld, Carl D., Harley, John B., Jacob, Chaim O., Namjou, Bahram, Sestak, Andrea L., Armstrong, Don L., Zidovetzki, Raphael, Kelly, Jennifer A., Jacob, Noam, Ciobanu, Voicu, Kaufman, Kenneth M., Ojwang, Joshua O., Ziegler, Julie, Quismorio, Francesco P., Reiff, Andreas, Myones, Barry L., Guthridge, Joel M., Nath, Swapan K., Bruner, Gail R., Mehrian-Shai, Ruth, Silverman, Earl, Klein-Gitelman, Marisa, McCurdy, Deborah, Wagner-Weiner, Linda, Nocton, James J., Putterman, Chaim, Bae, Sang-Cheol, Kim, Yun Jung, Petri, Michelle, Reveille, John D., Vyse, Timothy J., Gilkeson, Gary S., Kamen, Diane L., Alarcón-Riquelme, Marta E., Gaffney, Patrick M., Moser, Kathy L., Merrill, Joan T., Scofield, R. Hal, James, Judith A., Langefeld, Carl D., Harley, John B., and Jacob, Chaim O.

Abstract

OBJECTIVE: Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. METHODS: Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. RESULTS: We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 x 10(-25)). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4. CONCLUSION: Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.

Published
2009
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