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3. Management of Periprosthetic Joint Infection and Extensor Mechanism Disruption With Modular Knee Fusion: Clinical and Biomechanical Outcomes

Author

Wesley H. Mayes, MD, Anna C. Severin, PhD, Erin M. Mannen, PhD, Paul K. Edwards, MD, C. Lowry Barnes, MD, Jeffrey B. Stambough, MD, and Simon C. Mears, MD, PhD

Subjects
Prosthetic joint infection, Knee fusion, Gait analysis, Extensor mechanism failure, Orthopedic surgery, RD701-811
Abstract

Background: Extensor mechanism disruption (EMD) combined with periprosthetic joint infection (PJI) after total knee arthroplasty are life-changing complications. The literature suggests many eventually receive above-knee amputation and lose ambulatory function. An alternative is modular knee fusion (KF), but little is known about its outcomes and biomechanical function. We report early term results on a case series of patients. Methods: A retrospective review was conducted of patients who underwent 2-stage reconstruction with modular KF for combined EMD and PJI. Patient-reported outcomes at 1 year after arthrodesis and complications of surgery were recorded. Biomechanical analysis was conducted on 6 patients >1 year after surgery to measure gait speed and balance. Results: Fifteen patients received a modular KF. At the most recent follow-up visit (average 25.7 months), 12 patients had their modular KFs in place and were ambulatory while 2 had died. Six patients used a walker; 4, a cane; and 2, unassisted. Gait analysis of 6 of these patients showed variation in patterns and speed. Balance was better than historical controls treated with above-knee amputation. Average Knee Injury and Osteoarthritis Outcome Score Junior was 76 ± 11. Conclusion: Modular KF for EMD and PJI can result in successful outcomes in terms of preventing additional operations and maintaining ambulation. While speed is variable, physical testing shows this method for limb salvage may allow patients to ambulate with a gait aid although further studies are needed to evaluate midterm and long-term results.

Published
2021
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5. Management of Severe Proximal Femur Bone Loss With a Modular Articulating Antibiotic Spacer

Author

Wesley Mayes MD, Paul K. Edwards MD, and Simon C. Mears MD, PhD

Subjects
Orthopedic surgery, RD701-811, Geriatrics, RC952-954.6
Abstract

Introduction: Management of periprosthetic infection in total hip arthroplasties is challenging, especially when there is severe loss of proximal femoral bone stock. When a 2-stage approach is used, either a static or an articulating spacer may be considered. Static spacers leave the patient with a flail leg, which can be very difficult with massive bone loss. The purpose of this study is to report a novel technique for articulating antibiotic spacers and report our results. Materials and Methods: We describe a technique for an articulating hip spacer in the setting of a large amount of proximal femoral bone loss using a locked intramedullary nail, modular femoral body, and an all-polyethylene constrained acetabular component. This technique allowed for mobilization of the patient without a flail leg. Four patients underwent 2-stage reconstruction, and the case series is reported here. Results: No complications occurred due to the spacer, and in all cases, a second reconstruction was later carried out after treatment with intravenous antibiotics. Three of 4 patients did well after 2-stage reconstruction, with 1 patient ultimately requiring an amputation. Discussion: We feel this technique improves upon previously reported large spacers due to the stability and maintenance of leg length. Conclusion: This technique offers a modular solution to address massive bone loss of the proximal femur in the face of periprosthetic joint infection.

Published
2019
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7. Randomized feasibility trial of the Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program.

Author

Kwakkenbos, L, Østbø, N, Carrier, M-E, Nielson, WR, Fedoruk, C, Levis, B, Henry, RS, Pope, J, Frech, T, Gholizadeh, S, Johnson, SR, Piotrowski, P, Jewett, LR, Gordon, J, Chung, L, Bilsker, D, Tao, L, Turner, KA, Cumin, J, Welling, J, Fortuné, C, Leite, C, Gottesman, K, Sauvé, M, Reyna, TSR, Hudson, M, Larche, M, van Breda, W, Suarez-Almazor, ME, Bartlett, SJ, Malcarne, VL, Mayes, MD, Boutron, I, Mouthon, L, Benedetti, A, Thombs, BD, SPIN Investigators, Kwakkenbos, L, Østbø, N, Carrier, M-E, Nielson, WR, Fedoruk, C, Levis, B, Henry, RS, Pope, J, Frech, T, Gholizadeh, S, Johnson, SR, Piotrowski, P, Jewett, LR, Gordon, J, Chung, L, Bilsker, D, Tao, L, Turner, KA, Cumin, J, Welling, J, Fortuné, C, Leite, C, Gottesman, K, Sauvé, M, Reyna, TSR, Hudson, M, Larche, M, van Breda, W, Suarez-Almazor, ME, Bartlett, SJ, Malcarne, VL, Mayes, MD, Boutron, I, Mouthon, L, Benedetti, A, Thombs, BD, and SPIN Investigators

Abstract

BACKGROUND: The Scleroderma Patient-centered Intervention Network (SPIN) developed an online self-management program (SPIN-SELF) designed to improve disease-management self-efficacy in people with systemic sclerosis (SSc, or scleroderma). The aim of this study was to evaluate feasibility aspects for conducting a full-scale randomized controlled trial (RCT) of the SPIN-SELF Program. METHODS: This feasibility trial was embedded in the SPIN Cohort and utilized the cohort multiple RCT design. In this design, at the time of cohort enrollment, cohort participants consent to be assessed for trial eligibility and randomized prior to being informed about the trial. Participants in the intervention arm are informed and provide consent, but not the control group. Forty English-speaking SPIN Cohort participants from Canada, the USA, or the UK with low disease-management self-efficacy (Self-Efficacy for Managing Chronic Disease Scale [SEMCD] score ≤ 7) who were interested in using an online self-management program were randomized (3:2 ratio) to be offered the SPIN-SELF Program or usual care for 3 months. Program usage was examined via automated usage logs. User satisfaction was assessed with semi-structured interviews. Trial personnel time requirements and implementation challenges were logged. RESULTS: Of 40 SPIN Cohort participants randomized, 26 were allocated to SPIN-SELF and 14 to usual care. Automated eligibility and randomization procedures via the SPIN Cohort platform functioned properly, except that two participants with SEMCD scores > 7 (scores of 7.2 and 7.3, respectively) were included, which was caused by a system programming error that rounded SEMCD scores. Of 26 SPIN Cohort participants offered the SPIN-SELF Program, only 9 (35%) consented to use the program. Usage logs showed that use of the SPIN-SELF Program was low: 2 of 9 users (22%) logged into the program only once (median = 3), and 4 of 9 (44%) accessed none or only 1 of the 9 program's modules (median = 2)

Published
2022

8. Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes

Author

Hanson, AL, Sahhar, J, Ngian, G-S, Roddy, J, Walker, J, Stevens, W, Nikpour, M, Assassi, S, Proudman, S, Mayes, MD, Kenna, TJ, Brown, MA, Hanson, AL, Sahhar, J, Ngian, G-S, Roddy, J, Walker, J, Stevens, W, Nikpour, M, Assassi, S, Proudman, S, Mayes, MD, Kenna, TJ, and Brown, MA

Abstract

Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against diverse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of HLA inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01, previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an individual's underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.

Published
2022

9. The Effect of Body Fat Distribution on Systemic Sclerosis

Author

Villanueva-Martin, G, Acosta-Herrera, M, Kerick, M, Lopez-Isac, E, Simeon, CP, Callejas, JL, Assassi, S, Beretta, L, Allanore, Y, Proudman, SM, Nikpour, M, Fonseca, C, Denton, CP, Radstake, TRDJ, Mayes, MD, Jiang, X, Martin, J, Bossini-Castillo, L, Villanueva-Martin, G, Acosta-Herrera, M, Kerick, M, Lopez-Isac, E, Simeon, CP, Callejas, JL, Assassi, S, Beretta, L, Allanore, Y, Proudman, SM, Nikpour, M, Fonseca, C, Denton, CP, Radstake, TRDJ, Mayes, MD, Jiang, X, Martin, J, and Bossini-Castillo, L

Abstract

Obesity contributes to a chronic proinflammatory state, which is a known risk factor to develop immune-mediated diseases. However, its role in systemic sclerosis (SSc) remains to be elucidated. Therefore, we conducted a two-sample mendelian randomization (2SMR) study to analyze the effect of three body fat distribution parameters in SSc. As instrumental variables, we used the allele effects described for single nucleotide polymorphisms (SNPs) in different genome-wide association studies (GWAS) for SSc, body mass index (BMI), waist-to-hip ratio (WHR) and WHR adjusted for BMI (WHRadjBMI). We performed local (pHESS) and genome-wide (LDSC) genetic correlation analyses between each of the traits and SSc and we applied several Mendelian randomization (MR) methods (i.e., random effects inverse-variance weight, MR-Egger regression, MR pleiotropy residual sum and outlier method and a multivariable model). Our results show no genetic correlation or causal relationship between any of these traits and SSc. Nevertheless, we observed a negative causal association between WHRadjBMI and SSc, which might be due to the effect of gastrointestinal complications suffered by the majority of SSc patients. In conclusion, reverse causality might be an especially difficult confounding factor to define the effect of obesity in the onset of SSc.

Published
2022

10. Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Author

Kerick, M, Acosta-Herrera, M, Pilar Simeon-Aznar, C, Luis Callejas, J, Assassi, S, Proudman, SM, Nikpour, M, Hunzelmann, N, Moroncini, G, de Vries-Bouwstra, JK, Orozco, G, Barton, A, Herrick, AL, Terao, C, Allanore, Y, Fonseca, C, Eugenia Alarcon-Riquelme, M, Radstake, TRDJ, Beretta, L, Denton, CP, Mayes, MD, Martin, J, Kerick, M, Acosta-Herrera, M, Pilar Simeon-Aznar, C, Luis Callejas, J, Assassi, S, Proudman, SM, Nikpour, M, Hunzelmann, N, Moroncini, G, de Vries-Bouwstra, JK, Orozco, G, Barton, A, Herrick, AL, Terao, C, Allanore, Y, Fonseca, C, Eugenia Alarcon-Riquelme, M, Radstake, TRDJ, Beretta, L, Denton, CP, Mayes, MD, and Martin, J

Abstract

Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.

Published
2022

11. Effect of Nintedanib on Lung Function in Patients With Systemic Sclerosis-Associated Interstitial Lung Disease: Further Analyses of a Randomized, Double-Blind, Placebo-Controlled Trial

Author

Maher, TM, Mayes, MD, Kreuter, M, Volkmann, ER, Aringer, M, Castellvi, I, Cutolo, M, Stock, C, Schoof, N, Alves, M, Raghu, G, and SENSCIS Trial Investigators

Subjects
respiratory system, circulatory and respiratory physiology, respiratory tract diseases
Abstract

Objective In the SENSCIS trial in subjects with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) over 52 weeks by 44% versus placebo. This study was undertaken to investigate the effects of nintedanib on categorical changes in FVC and other measures of ILD progression. Methods In post hoc analyses, we assessed the proportions of subjects with categorical changes in FVC % predicted at week 52 and the time to absolute decline in FVC of >= 5% predicted or death and absolute decline in FVC of >= 10% predicted or death. Results A total of 288 subjects received nintedanib and 288 subjects received placebo. At week 52, in subjects treated with nintedanib and placebo, respectively, 55.7% and 66.3% had any decline in FVC % predicted, 13.6% and 20.1% had a decline in FVC of >5% to 10% to = 3.3% predicted (proposed minimal clinically important difference [MCID] for worsening of FVC), while 23.0% and 14.9% had an increase in FVC of >= 3.0% predicted (proposed MCID for improvement in FVC). Over 52 weeks, the hazard ratio (HR) for an absolute decline in FVC of >= 5% predicted or death with nintedanib versus placebo was 0.83 (95% confidence interval [95% CI] 0.66-1.06) (P = 0.14), and the HR for an absolute decline in FVC of >= 10% predicted was 0.64 (95% CI 0.43-0.95) (P = 0.029). Conclusion These results suggest that nintedanib has a clinically relevant benefit on the progression of SSc-ILD.

Published
2021

12. The Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program: protocol for a two-arm parallel partially nested randomized controlled feasibility trial with progression to full-scale trial.

Author

Nordlund, J, Henry, RS, Kwakkenbos, L, Carrier, M-E, Levis, B, Nielson, WR, Bartlett, SJ, Dyas, L, Tao, L, Fedoruk, C, Nielsen, K, Hudson, M, Pope, J, Frech, T, Gholizadeh, S, Johnson, SR, Piotrowski, P, Jewett, LR, Gordon, J, Chung, L, Bilsker, D, Levis, AW, Turner, KA, Cumin, J, Welling, J, Fortuné, C, Leite, C, Gottesman, K, Sauve, M, Rodríguez-Reyna, TS, Larche, M, van Breda, W, Suarez-Almazor, ME, Wurz, A, Culos-Reed, N, Malcarne, VL, Mayes, MD, Boutron, I, Mouthon, L, Benedetti, A, Thombs, BD, SPIN Investigators, Nordlund, J, Henry, RS, Kwakkenbos, L, Carrier, M-E, Levis, B, Nielson, WR, Bartlett, SJ, Dyas, L, Tao, L, Fedoruk, C, Nielsen, K, Hudson, M, Pope, J, Frech, T, Gholizadeh, S, Johnson, SR, Piotrowski, P, Jewett, LR, Gordon, J, Chung, L, Bilsker, D, Levis, AW, Turner, KA, Cumin, J, Welling, J, Fortuné, C, Leite, C, Gottesman, K, Sauve, M, Rodríguez-Reyna, TS, Larche, M, van Breda, W, Suarez-Almazor, ME, Wurz, A, Culos-Reed, N, Malcarne, VL, Mayes, MD, Boutron, I, Mouthon, L, Benedetti, A, Thombs, BD, and SPIN Investigators

Abstract

BACKGROUND: Systemic sclerosis (scleroderma; SSc) is a rare autoimmune connective tissue disease. We completed an initial feasibility trial of an online self-administered version of the Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program using the cohort multiple randomized controlled trial (RCT) design. Due to low intervention offer uptake, we will conduct a new feasibility trial with progression to full-scale trial, using a two-arm parallel, partially nested RCT design. The SPIN-SELF Program has also been revised to include facilitator-led videoconference group sessions in addition to online material. We will test the group-based intervention delivery format, then evaluate the effect of the SPIN-SELF Program on disease management self-efficacy (primary) and patient activation, social appearance anxiety, and functional health outcomes (secondary). METHODS: This study is a feasibility trial with progression to full-scale RCT, pending meeting pre-defined criteria, of the SPIN-SELF Program. Participants will be recruited from the ongoing SPIN Cohort ( http://www.spinsclero.com/en/cohort ) and via social media and partner patient organizations. Eligible participants must have SSc and low to moderate disease management self-efficacy (Self-Efficacy for Managing Chronic Disease (SEMCD) Scale score ≤ 7.0). Participants will be randomized (1:1 allocation) to the group-based SPIN-SELF Program or usual care for 3 months. The primary outcome in the full-scale trial will be disease management self-efficacy based on SEMCD Scale scores at 3 months post-randomization. Secondary outcomes include SEMCD scores 6 months post-randomization plus patient activation, social appearance anxiety, and functional health outcomes at 3 and 6 months post-randomization. We will include 40 participants to assess feasibility. At the end of the feasibility portion, stoppage criteria will be used to determine if the trial procedures or SPIN-SELF Program need important

Published
2021

13. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease

Author

Distler, O, Highland, Kb, Gahlemann, M, Azuma, A, Fischer, A, Mayes, Md, Raghu, G, Sauter, W, Girard, M, Alves, M, Clerisme-Beaty, E, Stowasser, S, Tetzlaff, K, Kuwana, M, Maher, Tm, Bergna, M, Casado, G, Mannucci Walter, P, Proudman, S, Stevens, W, Thakkar, V, Troy, L, Loeffler-Ragg, J, Olschewski, H, Bondue, B, Houssiau, F, Smith, V, Wuyts, W, Johnson, S, Keystone, E, Khalidi, N, Levesque, M, Maturana Rozas, R, Silva Orellana, A, Huang, C, Li, J, Jiang, Z, Liu, Y, Xiao, W, Xu, J, Zeng, X, Zheng, Y, Zou, H, Becvar, R, Madsen, H, Søndergaard, K, Kilpeläinen, M, Myllärniemi, M, Agard, C, Allanore, Y, Bourdin, A, Cottin, V, Crestani, B, Diot, E, Dominique, S, Hachulla, E, Jouneau, S, Leroy, S, Nunes, H, Prevot, G, Wallaert, B, Wemeau, L, Aringer, M, Bewig, B, Blaas, S, Distler, J, Ehrchen, J, Ewert, R, Gläser, S, Henes, J, Hunzelmann, N, König, R, Kötter, I, Kreuter, M, Prasse, A, Schulze-Koops, H, Sfikakis, P, Vlachoyiannopoulos, P, Losonczy, G, Behera, D, Gayathri Devi HJ, Kadel, J, Kawedia, M, Kumar, D, Kumar, U, Lokhande, R, Malpani, A, Mohan, M, Nalawade, A, Parakh, U, Swarnakar, R, Shobha, V, Thangakunam, B, Udwadia, Z, Henry, M, O'Reilly, K, Balbir-Gurman, A, Kramer, M, Litinsky, I, Rosner, I, Cutolo, M, Gabrielli, A, Iaccarino, L, Pesci, A, Riccieri, V, Vettori, S, Funakubo, Y, Inoue, Y, Kawakami, A, Kawaguchi, Y, Kawamura, T, Kondoh, Y, Nanki, T, Nishioka, Y, Nozawa, K, Oguragawa, T, Okamoto, M, Sano, H, Sasai, R, Sasaki, N, Suda, T, Takahashi, H, Takeuchi, T, Tanaka, S, Yamasaki, Y, Ch'Ng, Ss, Cheah, C, Kan, S, Raja Mohamed RB, Selman, M, de Vries-Bouwstra JK, van den Toorn, L, Vonken, M, Voskuyl, Ae, Hoffmann-Vold, Am, Seip, M, Dankiewicz-Fares, I, Olesiejuk, R, Pulka, G, Szepietowski, J, Alves, J, Bernardes, M, Cordeiro, A, Costa, J, Neves, S, Salvador, Mj, Alegre Sancho, J, Carreira Delgado, P, Castellví Barranco, I, Cifrián Martínez, J, Guillén Del Castillo, A, Ovalles, Jg, López-Longo, Fj, Rivera Gallego, A, Freire Dapena MC, Román Ivorra JA, Ekwall, Ah, Maurer, B, Mihai, Cm, Müller, R, Mahakkanukrauh, A, Nantiruj, K, Siripaitoon, B, Denton, Cp, Herrick, A, Madhok, R, West, A, Bascom, R, Criner, G, Csuka, Me, Dematte D'Amico, J, Ettinger, N, Gerbino, A, Gerke, A, Glassberg, M, Glazer, C, Golden, J, Gripaldo, R, Gupta, N, Hamblin, M, Highland, K, Ho, L, Huggins, Jt, Hummers, L, Jones, L, Kahaleh, M, Khanna, D, Kim, H, Lancaster, Lh, Luckhardt, T, Mayes, M, Mendoza Ballesteros, F, Mooney, J, Mohabir, P, Morrissey, B, Moua, T, Padilla, M, Patel, N, Perez, R, Roman, J, Rossman, M, Russell, T, Saketkoo, L, Shah, A, Shlobin, O, Scholand, Mb, Simmssetts, R, Spiera, R, Steen, V, Veeraraghavan, S, Weigt, S., Distler, O, Highland, Kb, Gahlemann, M, Azuma, A, Fischer, A, Mayes, Md, Raghu, G, Sauter, W, Girard, M, Alves, M, Clerisme-Beaty, E, Stowasser, S, Tetzlaff, K, Kuwana, M, Maher, Tm, SENSCIS Trial Investigators., Bergna M, Casado, G, Mannucci Walter, P, Proudman, S, Stevens, W, Thakkar, V, Troy, L, Loeffler-Ragg, J, Olschewski, H, Bondue, B, Houssiau, F, Smith, V, Wuyts, W, Johnson, S, Keystone, E, Khalidi, N, Levesque, M, Maturana Rozas, R, Silva Orellana, A, Huang, C, Li, J, Jiang, Z, Liu, Y, Xiao, W, Xu, J, Zeng, X, Zheng, Y, Zou, H, Becvar, R, Madsen, H, Søndergaard, K, Kilpeläinen, M, Myllärniemi, M, Agard, C, Allanore, Y, Bourdin, A, Cottin, V, Crestani, B, Diot, E, Dominique, S, Hachulla, E, Jouneau, S, Leroy, S, Nunes, H, Prevot, G, Wallaert, B, Wemeau, L, Aringer, M, Bewig, B, Blaas, S, Distler, J, Ehrchen, J, Ewert, R, Gläser, S, Henes, J, Hunzelmann, N, König, R, Kötter, I, Kreuter, M, Prasse, A, Schulze-Koops, H, Sfikakis, P, Vlachoyiannopoulos, P, Losonczy, G, Behera, D, Gayathri Devi, Hj, Kadel, J, Kawedia, M, Kumar, D, Kumar, U, Lokhande, R, Malpani, A, Mohan, M, Nalawade, A, Parakh, U, Swarnakar, R, Shobha, V, Thangakunam, B, Udwadia, Z, Henry, M, O'Reilly, K, Balbir-Gurman, A, Kramer, M, Litinsky, I, Rosner, I, Cutolo, M, Gabrielli, A, Iaccarino, Laura, Pesci, A, Riccieri, V, Vettori, S, Funakubo, Y, Inoue, Y, Kawakami, A, Kawaguchi, Y, Kawamura, T, Kondoh, Y, Nanki, T, Nishioka, Y, Nozawa, K, Oguragawa, T, Okamoto, M, Sano, H, Sasai, R, Sasaki, N, Suda, T, Takahashi, H, Takeuchi, T, Tanaka, S, Yamasaki, Y, Ch'Ng, S, Cheah, C, Kan, S, Raja Mohamed, Rb, Selman, M, de Vries-Bouwstra, Jk, van den Toorn, L, Vonken, M, Voskuyl, Ae, Hoffmann-Vold, Am, Seip, M, Dankiewicz-Fares, I, Olesiejuk, R, Pulka, G, Szepietowski, J, Alves, J, Bernardes, M, Cordeiro, A, Costa, J, Neves, S, Salvador, Mj, Alegre Sancho, J, Carreira Delgado, P, Castellví Barranco, I, Cifrián Martínez, J, Guillén Del Castillo, A, Ovalles, Jg, López-Longo, Fj, Rivera Gallego, A, Freire Dapena, Mc, Román Ivorra, Ja, Ekwall, Ah, Maurer, B, Mihai, Cm, Müller, R, Mahakkanukrauh, A, Nantiruj, K, Siripaitoon, B, Denton, Cp, Herrick, A, Madhok, R, West, A, Bascom, R, Criner, G, Csuka, Me, Dematte D'Amico, J, Ettinger, N, Gerbino, A, Gerke, A, Glassberg, M, Glazer, C, Golden, J, Gripaldo, R, Gupta, N, Hamblin, M, Highland, K, Ho, L, Huggins, Jt, Hummers, L, Jones, L, Kahaleh, M, Khanna, D, Kim, H, Lancaster, Lh, Luckhardt, T, Mayes, M, Mendoza Ballesteros, F, Mooney, J, Mohabir, P, Morrissey, B, Moua, T, Padilla, M, Patel, N, Perez, R, Roman, J, Rossman, M, Russell, T, Saketkoo, L, Shah, A, Shlobin, O, Scholand, Mb, Simmssetts, R, Spiera, R, Steen, V, Veeraraghavan, S, Weigt, S., National Institute for Health Research, British Lung Foundation, University of Zurich, and Distler, Oliver

Subjects
Male, Vital capacity, Indoles, Vital Capacity, Administration, Oral, 2700 General Medicine, 030204 cardiovascular system & hematology, Pulmonary function testing, law.invention, oral, Idiopathic pulmonary fibrosis, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, SENSCIS Trial Investigators, CYCLOPHOSPHAMIDE, Clinical endpoint, scleroderma, 030212 general & internal medicine, Enzyme Inhibitors, 11 Medical and Health Sciences, lung diseases, Lung Diseases, Interstitial -- drug therapy -- etiology -- physiopathology, 10051 Rheumatology Clinic and Institute of Physical Medicine, General Medicine, respiratory system, Sciences bio-médicales et agricoles, Middle Aged, Protein-Tyrosine Kinases, MANIFESTATIONS, Disease Progression, Nintedanib, Female, TYROSINE KINASE INHIBITOR, Life Sciences & Biomedicine, CLINICAL-TRIALS, Adult, Diarrhea, medicine.medical_specialty, FIBROBLASTS, 610 Medicine & health, Placebo, administration, behavioral disciplines and activities, 03 medical and health sciences, FEV1/FVC ratio, Medicine, General & Internal, Double-Blind Method, Internal medicine, General & Internal Medicine, Enzyme Inhibitors -- adverse effects -- therapeutic use, SCORE, medicine, Humans, Indoles -- adverse effects -- therapeutic use, Scleroderma, Systemic -- complications -- drug therapy, Science & Technology, Scleroderma, Systemic, Protein-Tyrosine Kinases -- antagonists & inhibitors, business.industry, MORTALITY, interstitial, PULMONARY-FUNCTION, systemic, STANDARDIZATION, medicine.disease, EFFICACY, respiratory tract diseases, body regions, chemistry, adult, diarrhea, disease progression, double-blind method, enzyme inhibitors, female, humans, indoles, lung diseases, interstitial, male, middle aged, protein-tyrosine kinases, scleroderma, systemic, vital capacity, business, Lung Diseases, Interstitial, Diarrhea -- chemically induced
Abstract

Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD., info:eu-repo/semantics/published

Published
2019

14. Protocol for a partially nested randomised controlled trial to evaluate the effectiveness of the scleroderma patient-centered intervention network COVID-19 home-isolation activities together (SPIN-CHAT) program to reduce anxiety among at-risk scleroderma patients

Author

Thombs, BD, Kwakkenbos, L, Carrier, M-E, Bourgeault, A, Tao, L, Harb, S, Gagarine, M, Rice, D, Bustamante, L, Ellis, K, Duchek, D, Wu, Y, Bhandari, PM, Neupane, D, Carboni-Jimenez, A, Henry, RS, Krishnan, A, Sun, Y, Levis, B, He, C, Turner, KA, Benedetti, A, Culos-Reed, N, El-Baalbaki, G, Hebblethwaite, S, Bartlett, SJ, Dyas, L, Patten, S, Varga, J, Fortune, C, Gietzen, A, Guillot, G, Lewis, N, Nielsen, K, Richard, M, Sauve, M, Welling, J, Baron, M, Furst, DE, Gottesman, K, Malcarne, V, Mayes, MD, Mouthon, L, Nielson, WR, Riggs, R, Wigley, F, Assassi, S, Boutron, I, Ells, C, van den Ende, C, Fligelstone, K, Frech, T, Godard, D, Harel, D, Hinchcliff, M, Hudson, M, Johnson, SR, Larche, M, Leite, C, Nguyen, C, Pope, J, Portales, A, Rannou, F, Rodriguez Reyna, TS, Schouffoer, AA, Suarez-Almazor, ME, Agard, C, Albert, A, Andre, M, Arsenault, G, Benzidia, I, Bernstein, EJ, Berthier, S, Bissonnette, L, Boire, G, Bruns, A, Carreira, P, Casadevall, M, Chaigne, B, Chung, L, Cohen, P, Correia, C, Dagenais, P, Denton, C, Domsic, R, Dubois, S, Dunne, J, Dunogue, B, Fare, R, Farge-Bancel, D, Fortin, PR, Gill, A, Gordon, J, Granel-Rey, B, Gyger, G, Hachulla, E, Hatron, P-Y, Herrick, AL, Hij, A, Hoa, S, Ikic, A, Jones, N, Fernandes, AJDB, Kafaja, S, Khalidi, N, Lambert, M, Launay, D, Liang, P, Maillard, H, Maltez, N, Manning, J, Marie, I, Martin, M, Martin, T, Masetto, A, Maurier, F, Mekinian, A, Melchor, S, Nikpour, M, Olagne, L, Poindron, V, Proudman, S, Regent, A, Riviere, S, Robinson, D, Rodriguez, E, Roux, S, Smets, P, Smith, D, Sobanski, V, Spiera, R, Steen, V, Stevens, W, Sutton, E, Terrier, B, Thorne, C, Wilcox, P, Ayala, MC, Ostbo, N, Thombs, BD, Kwakkenbos, L, Carrier, M-E, Bourgeault, A, Tao, L, Harb, S, Gagarine, M, Rice, D, Bustamante, L, Ellis, K, Duchek, D, Wu, Y, Bhandari, PM, Neupane, D, Carboni-Jimenez, A, Henry, RS, Krishnan, A, Sun, Y, Levis, B, He, C, Turner, KA, Benedetti, A, Culos-Reed, N, El-Baalbaki, G, Hebblethwaite, S, Bartlett, SJ, Dyas, L, Patten, S, Varga, J, Fortune, C, Gietzen, A, Guillot, G, Lewis, N, Nielsen, K, Richard, M, Sauve, M, Welling, J, Baron, M, Furst, DE, Gottesman, K, Malcarne, V, Mayes, MD, Mouthon, L, Nielson, WR, Riggs, R, Wigley, F, Assassi, S, Boutron, I, Ells, C, van den Ende, C, Fligelstone, K, Frech, T, Godard, D, Harel, D, Hinchcliff, M, Hudson, M, Johnson, SR, Larche, M, Leite, C, Nguyen, C, Pope, J, Portales, A, Rannou, F, Rodriguez Reyna, TS, Schouffoer, AA, Suarez-Almazor, ME, Agard, C, Albert, A, Andre, M, Arsenault, G, Benzidia, I, Bernstein, EJ, Berthier, S, Bissonnette, L, Boire, G, Bruns, A, Carreira, P, Casadevall, M, Chaigne, B, Chung, L, Cohen, P, Correia, C, Dagenais, P, Denton, C, Domsic, R, Dubois, S, Dunne, J, Dunogue, B, Fare, R, Farge-Bancel, D, Fortin, PR, Gill, A, Gordon, J, Granel-Rey, B, Gyger, G, Hachulla, E, Hatron, P-Y, Herrick, AL, Hij, A, Hoa, S, Ikic, A, Jones, N, Fernandes, AJDB, Kafaja, S, Khalidi, N, Lambert, M, Launay, D, Liang, P, Maillard, H, Maltez, N, Manning, J, Marie, I, Martin, M, Martin, T, Masetto, A, Maurier, F, Mekinian, A, Melchor, S, Nikpour, M, Olagne, L, Poindron, V, Proudman, S, Regent, A, Riviere, S, Robinson, D, Rodriguez, E, Roux, S, Smets, P, Smith, D, Sobanski, V, Spiera, R, Steen, V, Stevens, W, Sutton, E, Terrier, B, Thorne, C, Wilcox, P, Ayala, MC, and Ostbo, N

Abstract

Objective Contagious disease outbreaks and related restrictions can lead to negative psychological outcomes, particularly in vulnerable populations at risk due to pre-existing medical conditions. No randomised controlled trials (RCTs) have tested interventions to reduce mental health consequences of contagious disease outbreaks. The primary objective of the Scleroderma Patient-centered Intervention Network COVID-19 Home-isolation Activities Together (SPIN-CHAT) Trial is to evaluate the effect of a videoconference-based program on symptoms of anxiety. Secondary objectives include evaluating effects on symptoms of depression, stress, loneliness, boredom, physical activity, and social interaction.

Published
2020

15. Changes in mental health symptoms from pre-COVID-19 to COVID-19 among participants with systemic sclerosis from four countries: A Scleroderma Patient-centered Intervention Network (SPIN) Cohort study

Author

Thombs, BD, Kwakkenbos, L, Henry, RS, Carrier, M-E, Patten, S, Harb, S, Bourgeault, A, Tao, L, Bartlett, SJ, Mouthon, L, Varga, J, Benedetti, A, Fortune, C, Gietzen, A, Guillot, G, Lewis, N, Richard, M, Sauve, M, Welling, J, Fligelstone, K, Gottesman, K, Leite, C, Perez, E, Baron, M, Malcarne, V, Mayes, MD, Nielson, WR, Riggs, R, Assassi, S, Ells, C, van den Ende, C, Frech, T, Harel, D, Hinchcliff, M, Hudson, M, Johnson, SR, Larche, M, Nguyen, C, Pope, J, Rannou, F, Reyna, TSR, Schouffoer, AA, Suarez-Almazor, ME, Agard, C, Albert, A, Bernstein, EJ, Berthier, S, Bissonnette, L, Bruns, A, Carreira, P, Chaigne, B, Chung, L, Correia, C, Denton, C, Domsic, R, Dunne, J, Dunogue, B, Farge-Bancel, D, Fortin, PR, Gordon, J, Granel-Rey, B, Hatron, P-Y, Herrick, AL, Hoa, S, Jones, N, Fernandes, AJDB, Kafaja, S, Khalidi, N, Launay, D, Manning, J, Marie, I, Martin, M, Mekinian, A, Melchor, S, Nikpour, M, Olagne, L, Proudman, S, Regent, A, Riviere, S, Robinson, D, Rodriguez, E, Roux, S, Sobanski, V, Steen, V, Sutton, E, Thorne, C, Wilcox, P, Ayala, MC, Carboni-Jimenez, A, Gagarine, M, Nordlund, J, Ostbo, N, Rice, DB, Turner, KA, Culos-Reed, N, Dyas, L, El-Baalbaki, G, Hebblethwaite, S, Bustamante, L, Duchek, D, Ellis, K, Thombs, BD, Kwakkenbos, L, Henry, RS, Carrier, M-E, Patten, S, Harb, S, Bourgeault, A, Tao, L, Bartlett, SJ, Mouthon, L, Varga, J, Benedetti, A, Fortune, C, Gietzen, A, Guillot, G, Lewis, N, Richard, M, Sauve, M, Welling, J, Fligelstone, K, Gottesman, K, Leite, C, Perez, E, Baron, M, Malcarne, V, Mayes, MD, Nielson, WR, Riggs, R, Assassi, S, Ells, C, van den Ende, C, Frech, T, Harel, D, Hinchcliff, M, Hudson, M, Johnson, SR, Larche, M, Nguyen, C, Pope, J, Rannou, F, Reyna, TSR, Schouffoer, AA, Suarez-Almazor, ME, Agard, C, Albert, A, Bernstein, EJ, Berthier, S, Bissonnette, L, Bruns, A, Carreira, P, Chaigne, B, Chung, L, Correia, C, Denton, C, Domsic, R, Dunne, J, Dunogue, B, Farge-Bancel, D, Fortin, PR, Gordon, J, Granel-Rey, B, Hatron, P-Y, Herrick, AL, Hoa, S, Jones, N, Fernandes, AJDB, Kafaja, S, Khalidi, N, Launay, D, Manning, J, Marie, I, Martin, M, Mekinian, A, Melchor, S, Nikpour, M, Olagne, L, Proudman, S, Regent, A, Riviere, S, Robinson, D, Rodriguez, E, Roux, S, Sobanski, V, Steen, V, Sutton, E, Thorne, C, Wilcox, P, Ayala, MC, Carboni-Jimenez, A, Gagarine, M, Nordlund, J, Ostbo, N, Rice, DB, Turner, KA, Culos-Reed, N, Dyas, L, El-Baalbaki, G, Hebblethwaite, S, Bustamante, L, Duchek, D, and Ellis, K

Abstract

INTRODUCTION: No studies have reported mental health symptom comparisons prior to and during COVID-19 in vulnerable medical populations. OBJECTIVE: To compare anxiety and depression symptoms among people with a pre-existing medical condition and factors associated with changes. METHODS: Pre-COVID-19 Scleroderma Patient-centered Intervention Network Cohort data were linked to COVID-19 data from April 2020. Multiple linear and logistic regression were used to assess factors associated with continuous change and ≥ 1 minimal clinically important difference (MCID) change for anxiety (PROMIS Anxiety 4a v1.0; MCID = 4.0) and depression (Patient Health Questionnaire-8; MCID = 3.0) symptoms, controlling for pre-COVID-19 levels. RESULTS: Mean anxiety symptoms increased 4.9 points (95% confidence interval [CI] 4.0 to 5.7). Depression symptom change was negligible (0.3 points; 95% CI -0.7 to 0.2). Compared to France (N = 159), adjusted anxiety symptom change scores were significantly higher in the United Kingdom (N = 50; 3.3 points, 95% CI 0.9 to 5.6), United States (N = 128; 2.5 points, 95% CI 0.7 to 4.2), and Canada (N = 98; 1.9 points, 95% CI 0.1 to 3.8). Odds of ≥1 MCID increase were 2.6 for the United Kingdom (95% CI 1.2 to 5.7) but not significant for the United States (1.6, 95% CI 0.9 to 2.9) or Canada (1.4, 95% CI 0.7 to 2.5). Older age and adequate financial resources were associated with less continuous anxiety increase. Employment and shorter time since diagnosis were associated with lower odds of a ≥ 1 MCID increase. CONCLUSIONS: Anxiety symptoms, but not depression symptoms, increased dramatically during COVID-19 among people with a pre-existing medical condition.

Published
2020

16. Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis

Author

Diaz-Gallo, LM, Gourh, P, Broen, J, Simeon, C, Fonollosa, V, Ortego-Centeno, N, Agarwal, S, Vonk, MC, Coenen, M, Riemekasten, G, Hunzelmann, N, Hesselstrand, R, Tan, FK, Reveille, JD, Assassi, S, García-Hernandez, FJ, Carreira, P, Camps, MT, Fernandez-Nebro, A, de la Peña, P Garcia, Nearney, T, Hilda, D, González-Gay, MA, Airo, P, Beretta, L, Scorza, R, Herrick, A, Worthington, J, Pros, A, Gómez-Gracia, I, Trapiella, L, Espinosa, G, Castellvi, I, Witte, T, de Keyser, F, Vanthuyne, M, Mayes, MD, Radstake, TRDJ, Arnett, FC, Martin, J, and Rueda, B

Published
2011
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22. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways

Author

Lopez-Isac, E, Acosta-Herrera, M, Kerick, M, Assassi, S, Satpathy, AT, Granja, J, Mumbach, MR, Beretta, L, Simeon, CP, Carreira, P, Ortego-Centeno, N, Castellvi, I, Bossini-Castillo, L, David Carmona, F, Orozco, G, Hunzelmann, N, Distler, JHW, Franke, A, Lunardi, C, Moroncini, G, Gabrielli, A, de Vries-Bouwstra, J, Wijmenga, C, Koeleman, BPC, Nordin, A, Padyukov, L, Hoffmann-Vold, A-M, Lie, B, Rios, R, Callejas, JL, Vargas-Hitos, JA, Garcia-Portales, R, Camps, MT, Fernandez-Nebro, A, Gonzalez-Escribano, MF, Garcia-Hernandez, FJ, Castillo, MJ, Aguirre, MA, Gomez-Gracia, I, Fernandez-Gutierrez, B, Rodriguez-Rodriguez, L, Garcia de la Pena, P, Vicente, E, Andreu, JL, Fernandez de Castro, M, Lopez-Longo, FJ, Martinez, L, Fonollosa, V, Guillen, A, Espinosa, G, Tolosa, C, Pros, A, Rodriguez-Carballeira, M, Narvaez, FJ, Rubio-Rivas, M, Ortiz-Santamaria, V, Madronero, AB, Gonzalez-Gay, MA, Diaz, B, Trapiella, L, Sousa, A, Egurbide, MV, Fanlo-Mateo, P, Saez-Comet, L, Diaz, F, Hernandez, V, Beltran, E, Roman-Ivorra, JA, Grau, E, Alegre-Sancho, JJ, Freire, M, Blanco-Garcia, FJ, Oreiro, N, Witte, T, Kreuter, A, Riemekasten, G, Airo, P, Magro, C, Voskuyl, AE, Vonk, MC, Hesselstrand, R, Proudman, S, Stevens, W, Nikpour, M, Zochling, J, Sahhar, J, Roddy, J, Nash, P, Tymms, K, Rischmueller, M, Lester, S, Vyse, T, Herrick, AL, Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, TRDJ, Fonseca, C, Chang, HY, Mayes, MD, Martin, J, Lopez-Isac, E, Acosta-Herrera, M, Kerick, M, Assassi, S, Satpathy, AT, Granja, J, Mumbach, MR, Beretta, L, Simeon, CP, Carreira, P, Ortego-Centeno, N, Castellvi, I, Bossini-Castillo, L, David Carmona, F, Orozco, G, Hunzelmann, N, Distler, JHW, Franke, A, Lunardi, C, Moroncini, G, Gabrielli, A, de Vries-Bouwstra, J, Wijmenga, C, Koeleman, BPC, Nordin, A, Padyukov, L, Hoffmann-Vold, A-M, Lie, B, Rios, R, Callejas, JL, Vargas-Hitos, JA, Garcia-Portales, R, Camps, MT, Fernandez-Nebro, A, Gonzalez-Escribano, MF, Garcia-Hernandez, FJ, Castillo, MJ, Aguirre, MA, Gomez-Gracia, I, Fernandez-Gutierrez, B, Rodriguez-Rodriguez, L, Garcia de la Pena, P, Vicente, E, Andreu, JL, Fernandez de Castro, M, Lopez-Longo, FJ, Martinez, L, Fonollosa, V, Guillen, A, Espinosa, G, Tolosa, C, Pros, A, Rodriguez-Carballeira, M, Narvaez, FJ, Rubio-Rivas, M, Ortiz-Santamaria, V, Madronero, AB, Gonzalez-Gay, MA, Diaz, B, Trapiella, L, Sousa, A, Egurbide, MV, Fanlo-Mateo, P, Saez-Comet, L, Diaz, F, Hernandez, V, Beltran, E, Roman-Ivorra, JA, Grau, E, Alegre-Sancho, JJ, Freire, M, Blanco-Garcia, FJ, Oreiro, N, Witte, T, Kreuter, A, Riemekasten, G, Airo, P, Magro, C, Voskuyl, AE, Vonk, MC, Hesselstrand, R, Proudman, S, Stevens, W, Nikpour, M, Zochling, J, Sahhar, J, Roddy, J, Nash, P, Tymms, K, Rischmueller, M, Lester, S, Vyse, T, Herrick, AL, Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, TRDJ, Fonseca, C, Chang, HY, Mayes, MD, and Martin, J

Abstract

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

Published
2019

23. Generation of a Core Set of Items to Develop Classification Criteria for Scleroderma Renal Crisis Using Consensus Methodology

Author

Butler, E-A, Baron, M, Fogo, AB, Frech, T, Ghossein, C, Hachulla, E, Hoa, S, Johnson, SR, Khanna, D, Mouthon, L, Nikpour, M, Proudman, S, Steen, V, Stern, E, Varga, J, Denton, C, Hudson, M, Barnado, A, Bernstein, EJ, Boin, F, Braun-Moscovici, Y, Castelino, FV, Catoggio, LJ, Matucci-Cerinic, M, Chung, L, Clements, P, Csuka, ME, De langhe, E, Distler, J, Distler, O, Farge, DC, Fischer, A, Gabrielli, A, Hasegawa, M, Hayat, S, Herrick, A, Hesselstrand, R, Hsu, V, Hughes, M, Hunzelmann, N, Hummers, L, Iannone, F, Ingegnoli, F, Jacobsen, S, Kawaguchi, Y, Koenig, M, Kuwana, M, Lenaerts, J, Martin, T, Mayes, MD, McMahan, Z, Medsger, T, Merkel, P, Narain, S, Ong, V, Pauling, JD, Pope, J, de la Puente, C, Rischmueller, M, Sofia Rodriguez-Reyna, T, Sahhar, J, Saketkoo, LA, Senecal, J-L, Shah, A, Shah, AA, Alberto Sifuentes-Giraldo, W, Silver, R, Stevens, W, Sutton, E, Thakkar, V, Valentini, G, de Vries-Bouwstra, J, Vonk, M, Walker, UA, Butler, E-A, Baron, M, Fogo, AB, Frech, T, Ghossein, C, Hachulla, E, Hoa, S, Johnson, SR, Khanna, D, Mouthon, L, Nikpour, M, Proudman, S, Steen, V, Stern, E, Varga, J, Denton, C, Hudson, M, Barnado, A, Bernstein, EJ, Boin, F, Braun-Moscovici, Y, Castelino, FV, Catoggio, LJ, Matucci-Cerinic, M, Chung, L, Clements, P, Csuka, ME, De langhe, E, Distler, J, Distler, O, Farge, DC, Fischer, A, Gabrielli, A, Hasegawa, M, Hayat, S, Herrick, A, Hesselstrand, R, Hsu, V, Hughes, M, Hunzelmann, N, Hummers, L, Iannone, F, Ingegnoli, F, Jacobsen, S, Kawaguchi, Y, Koenig, M, Kuwana, M, Lenaerts, J, Martin, T, Mayes, MD, McMahan, Z, Medsger, T, Merkel, P, Narain, S, Ong, V, Pauling, JD, Pope, J, de la Puente, C, Rischmueller, M, Sofia Rodriguez-Reyna, T, Sahhar, J, Saketkoo, LA, Senecal, J-L, Shah, A, Shah, AA, Alberto Sifuentes-Giraldo, W, Silver, R, Stevens, W, Sutton, E, Thakkar, V, Valentini, G, de Vries-Bouwstra, J, Vonk, M, and Walker, UA

Abstract

OBJECTIVE: To generate a core set of items to develop classification criteria for scleroderma renal crisis (SRC) using consensus methodology. METHODS: An international, multidisciplinary panel of experts was invited to participate in a 3-round Delphi exercise developed using a survey based on items identified by a scoping review. In round 1, participants were asked to identify omissions and clarify ambiguities regarding the items in the survey. In round 2, participants were asked to rate the validity and feasibility of the items using Likert-type scales ranging from 1 to 9 (where 1 = very invalid/unfeasible, 5 = uncertain, and 9 = very valid/feasible). In round 3, participants reviewed the results and comments from round 2 and were asked to provide final ratings. Items rated as highly valid and feasible (median scores ≥7 for each) in round 3 were selected as the provisional core set of items. A consensus meeting using a nominal group technique was conducted to further reduce the core set of items. RESULTS: Ninety-nine experts from 16 countries participated in the Delphi exercise. Of the 31 items in the survey, consensus was achieved on 13, in the categories hypertension, renal insufficiency, proteinuria, and hemolysis. Eleven experts took part in the nominal group technique discussion, where consensus was achieved in 5 domains: blood pressure, acute kidney injury, microangiopathic hemolytic anemia, target organ dysfunction, and renal histopathology. CONCLUSION: A core set of items that characterize SRC was identified using consensus methodology. This core set will be used in future data-driven phases of this project to develop classification criteria for SRC.

Published
2019

24. Meta-analysis of Immunochip data of four autoimmune diseases reveals novel single-disease and cross-phenotype associations

Author

Marquez, A, Kerick, M, Zhernakova, A, Gutierrez-Achury, J, Chen, W, Onengut-Gumuscu, S, Gonzalez-Alvaro, I, Rodriguez-Rodriguez, L, Rios-Fernandez, R, Gonzalez-Gay, M, Mayes, M, Raychaudhuri, S, Rich, S, Wijmenga, C, Martin, J, Barisani, D, Chen, WM, Gonzalez-Gay, MA, Mayes, MD, Rich, SS, Marquez, A, Kerick, M, Zhernakova, A, Gutierrez-Achury, J, Chen, W, Onengut-Gumuscu, S, Gonzalez-Alvaro, I, Rodriguez-Rodriguez, L, Rios-Fernandez, R, Gonzalez-Gay, M, Mayes, M, Raychaudhuri, S, Rich, S, Wijmenga, C, Martin, J, Barisani, D, Chen, WM, Gonzalez-Gay, MA, Mayes, MD, and Rich, SS

Abstract

Background: In recent years, research has consistently proven the occurrence of genetic overlap across autoimmune diseases, which supports the existence of common pathogenic mechanisms in autoimmunity. The objective of this study was to further investigate this shared genetic component. Methods: For this purpose, we performed a cross-disease meta-analysis of Immunochip data from 37,159 patients diagnosed with a seropositive autoimmune disease (11,489 celiac disease (CeD), 15,523 rheumatoid arthritis (RA), 3477 systemic sclerosis (SSc), and 6670 type 1 diabetes (T1D)) and 22,308 healthy controls of European origin using the R package ASSET. Results: We identified 38 risk variants shared by at least two of the conditions analyzed, five of which represent new pleiotropic loci in autoimmunity. We also identified six novel genome-wide associations for the diseases studied. Cell-specific functional annotations and biological pathway enrichment analyses suggested that pleiotropic variants may act by deregulating gene expression in different subsets of T cells, especially Th17 and regulatory T cells. Finally, drug repositioning analysis evidenced several drugs that could represent promising candidates for CeD, RA, SSc, and T1D treatment. Conclusions: In this study, we have been able to advance in the knowledge of the genetic overlap existing in autoimmunity, thus shedding light on common molecular mechanisms of disease and suggesting novel drug targets that could be explored for the treatment of the autoimmune diseases studied

Published
2018

25. Insights into the genetic basis of systemic sclerosis: immunity in human disease and in mouse models

Author

Wu M and Mayes MD

Subjects
lcsh:Genetics, lcsh:QH426-470
Abstract

Minghua Wu, Maureen D Mayes Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX, USA Abstract: Systemic sclerosis (SSc; scleroderma) is a chronic, multisystem autoimmune disease characterized by vasculopathy, fibrosis, and autoantibodies. In the past decade, great efforts have been made to investigate genetic susceptibility for SSc. To date, over 20 gene loci have been identified as risk factors for SSc in large genome-wide association studies and confirmed by independent replication studies. However, the biological relevance of these genetic associations is still largely unknown. Exploring the mechanism behind these risk loci is essential to better understand disease pathogenesis and to identify novel therapeutic targets. Mouse model studies including knockout, knockin and knockdown of these genes can advance our understanding of pathogenic cellular and molecular mechanisms in human disease. Although such mouse model systems do not exactly correspond to human disease, they can provide insight into pathological mechanisms that influence disease pathways. In this review, we discuss recent findings regarding the genetic basis of SSc in the setting of genetic manipulation of these pathways in murine models. Keywords: GWAS, Immunochip study, type I interferon pathway, genetic mutation animal models

Published
2014

26. Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

Author

López-Isac E, Martín JE, Assassi S, Simeón CP, Carreira P, Ortego-Centeno N, Freire M, Beltrán E, Narváez J, Alegre-Sancho JJ, Spanish Scleroderma Group, Fernández-Gutiérrez B, Balsa A, Ortiz AM, González-Gay MA, Beretta L, Santaniello A, Bellocchi C, Lunardi C, Moroncini G, Gabrielli A, Witte T, Hunzelmann N, Distler JH, Riekemasten G, van der Helm-van Mil AH, de Vries-Bouwstra J, Magro-Checa C, Voskuyl AE, Vonk MC, Molberg Ø, Merriman T, Hesselstrand R, Nordin A, Padyukov L, Herrick A, Eyre S, Koeleman BP, Denton CP, Fonseca C, Radstake TR, Worthington J, Mayes MD, Martín J, University of Queensland [Brisbane], Rheumatology Service, Hospital Clínico San Carlos, University Hospital La Paz, Madrid, Referral Center for Systemic Autoimmune Diseases, University of Milan, Department of Clinical and Experimental Medicine, University of Verona (UNIVR), Department of Dermatology, University of Cologne, Department of Internal Medicine 3, Institute for Clinical Immunology Erlangen-Nuremberg, Karolinska Institutet [Stockholm], University Medical Center [Utrecht], Laboratory of Translational Immunology [Utrecht, the Netherlands], Institute of Parasitology and Biomedicine (IPB - GRANADA), Spanish National Research Council (CSIC), Immunologie et Pathologie (EA 2216), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Brest, and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, Scleroderma, Systemic, integumentary system, [SDV]Life Sciences [q-bio], Arthritis, Rheumatoid, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Genetic Loci, Risk Factors, Interferon Regulatory Factors, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract

Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy. The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.

Published
2016

27. Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis

Author

Khanna, D, Denton, Cp, Merkel, Pa, Krieg, T, Le Brun FO, Marr, A, Papadakis, K, Pope, J, Matucci Cerinic, M, Furst, De, Zochling, J, Stevens, W, Proudman, S, Feenstra, J, Youssef, P, Soroka, N, Tyabut, T, Mikhailova, Ei, Rashkov, R, Batalov, A, Yablanski, K, Keystone, E, Jones, N, Dunne, J, Masetto, A, Calabresse, Rj, Cabezas, Pc, Silva, Mo, Sariego, Ia, Escalente, Wj, Anić, B, Kaliterna, Dm, Morović Vergles, J, Novak, S, Prus, V, Artuković, M, Soukup, T, Bečvař, R, Fojtík, Z, Mouthon, L, Kollert, F, Krieg, Tm, Riemekasten, G, Lahner, N, Fierlbeck, G, Ahmadi Simab, K, Diehm, C, Szücs, G, Kumánovics, G, Nagy, G, Pal, S, Veeravalli, Sc, Danda, D, Ferri, Clodoveo, Cerinic, Mm, Cozzi, F, Ferraccioli, G, Wiland, P, Rudnicak, L, Zwolak, R, Roszkiewicz, J, Oleynikov, V, Nikulenkova, N, Lesnyak, O, Kaydashev, I, Kurytar, O, Piura, O, Chopyak, V, Chatterjee, S, Hsu, V, Hummers, L, Martin, R, Domsic, R, Schiopu, E, Shanahan, J, Murphy, Ft, Kaine, J, Davis, W, Grau, R, Eimon, A, Catoggio, Lj, Laborde, Ha, Caeiro, F, Savio, Vg, Amitrano, Cb, Vanthuyne, M, Zeng, X, Zhang, X, Zhu, P, Velásquez Franco CJ, Choueka, Ps, Sanchez, Pj, Hermann, W, Sticherling, M, Steinbrink, K, Hein, R, Aschoff, R, Sfikakis, P, Settas, L, Fraser, A, Veale, D, Balbir Gurman, A, Lidar, M, Litinsky, I, Levy, Y, Carrillo Vazquez SM, Rodriguez Reyna, T, Medrano Ramirez, G, Morales Torres, J, Pacheco Tena CF, Sanchez Ortiz, A, Vonk, Mc, Stebbings, S, Solanki, K, Steele, R, Ng, Kp, Zubrzycka Sienkiewicz, A, Brzosko, M, Szepietowski, Jc, Hrycaj, P, da Silva IF, dos Santos Lda, C, Coelho, Pj, Rios, G, Chernykh, T, Grunina, E, Stanislav, M, Ally, M, Kalla, A, Birlik, Am, Kovalenko, V, Petrov, A, Shevchuk, S, Stanislavchuk, M, Anderson, M, Herrick, A, Belch, J, Chung, L, Csuka, Me, Frech, T, Goldberg, A, Kahaleh, B, Mayes, Md, Rothfield, N, Simms, Rw, Spiera, R, Steen, V, Varga, J, Sikes, D, Derk, Ct, Kohen, M. D., and UCL - (SLuc) Service de rhumatologie

Subjects
0301 basic medicine, Male, Settore MED/16 - REUMATOLOGIA, systemic sclerosis, Peripheral edema, Administration, Oral, law.invention, Scleroderma, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Interna medicina, Sulfonamides, Endothelin-1, Medicine (all), General Medicine, Middle Aged, Administration, Female, medicine.symptom, BIOMEDICINA I ZDRAVSTVO. Temeljne medicinske znanosti, Oral, medicine.medical_specialty, Double-Blind Method, Fingers, Humans, Outcome Assessment (Health Care), Pyrimidines, Scleroderma, Systemic, Skin Ulcer, Anemia, Macitentan, Digital Ulcers, Systemic Sclerosis, Placebo, 03 medical and health sciences, Internal medicine, medicine, Adverse effect, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Internal Medicine, Macitentan, 030203 arthritis & rheumatology, business.industry, BIOMEDICINE AND HEALTHCARE. Basic Medical Sciences, Systemic, Skin ulcer, medicine.disease, Surgery, Clinical trial, 030104 developmental biology, chemistry, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], business
Abstract

Contains fulltext : 172407.pdf (Publisher’s version ) (Closed access) IMPORTANCE: Digital ulcers in patients with systemic sclerosis are associated with pain and poor quality of life. Endothelin-1 promotes vasculopathy in systemic sclerosis after macitentan, an endothelin-1 blocker. OBJECTIVE: To evaluate the efficacy of macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis. DESIGN, SETTING, AND PARTICIPANTS: Two international, randomized, double-blind, placebo-controlled trials (DUAL-1, DUAL-2) were conducted between January 2012 and February 2014. Participants were patients with systemic sclerosis and active digital ulcers at baseline. Target enrollment for each study was 285 patients. INTERVENTIONS: Patients were randomized (1:1:1) to receive oral doses of 3 mg of macitentan, 10 mg of macitentan, or placebo once daily and stratified according to number of digital ulcers at baseline (3). MAIN OUTCOMES AND MEASURES: The primary outcome for each trial was the cumulative number of new digital ulcers from baseline to week 16. Treatment effect was expressed as the ratio between treatment groups. RESULTS: In DUAL-1, among 289 randomized patients (mean age 51.2 years; 85.8% women), 226 completed the study. The adjusted mean number of new digital ulcers per patient over 16 weeks was 0.94 in the 3-mg macitentan group (n = 95) and 1.08 in the 10-mg macitentan group (n = 97) compared with 0.85 in the placebo group (n = 97) (absolute difference, 0.09 [95% CI, -0.37 to 0.54] for 3 mg of macitentan vs placebo and 0.23 [-0.27 to 0.72] for 10 mg of macitentan vs placebo). Among 265 patients randomized in DUAL-2 (mean age 49.6 years; 81.9% women), 216 completed the study. In DUAL-2, the adjusted mean number of new digital ulcers was 1.44 in the 3-mg macitentan group (n = 88) and 1.46 in the 10-mg macitentan group (n = 88) compared with 1.21 in the placebo group (n = 89) (absolute difference, 0.23 [95% CI, -0.35 to 0.82] for 3 mg of macitentan vs placebo and 0.25 [95% CI, -0.34 to 0.84] for 10 mg of macitentan vs placebo). Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis. CONCLUSIONS AND RELEVANCE: Among patients with systemic sclerosis and active ischemic digital ulcers, treatment with macitentan did not reduce new digital ulcers over 16 weeks. These results do not support the use of macitentan for the treatment of digital ulcers in this patient population. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01474109, NCT01474122.

Published
2016

28. Single-specificity anti-Ku antibodies in an international cohort of 2140 systemic sclerosis subjects: clinical associations

Author

Hoa, S, Hudson, M, Troyanov, Y, Proudman, S, Walker, J, Stevens, W, Nikpour, M, Assassi, S, Mayes, MD, Wang, M, Baron, M, Fritzler, MJ, Hoa, S, Hudson, M, Troyanov, Y, Proudman, S, Walker, J, Stevens, W, Nikpour, M, Assassi, S, Mayes, MD, Wang, M, Baron, M, and Fritzler, MJ

Abstract

Autoantibodies directed against the Ku autoantigen are present in systemic sclerosis (SSc) and have been associated with myositis overlap and interstitial lung disease (ILD). However, there is a paucity of data on the clinical correlates of anti-Ku antibodies in the absence of other SSc-specific antibodies. The aim of this study was to assess the clinical correlates of single-specificity anti-Ku in SSc.An international (Canada, Australia, USA, Mexico) cohort of 2140 SSc subjects was formed, demographic and clinical variables were harmonized, and sera were tested for anti-Ku using a line immunoassay. Associations between single-specificity anti-Ku antibodies (i.e., in isolation of other SSc-specific antibodies) and outcomes of interest, including myositis, ILD, and survival, were investigated.Twenty-four (1.1%) subjects had antibodies against Ku, and 13 (0.6%) had single-specificity anti-Ku antibodies. Subjects with single-specificity anti-Ku antibodies were more likely to have ILD (58% vs 34%), and to have increased creatine kinase levels (>3× normal) at baseline (11% vs 1%) and during follow-up (10% vs 2%). No difference in survival was noted in subjects with and without single-specificity anti-Ku antibodies.This is the largest cohort to date focusing on the prevalence and disease characteristics of single-specificity anti-Ku antibodies in subjects with SSc. These results need to be interpreted with caution in light of the small sample. International collaboration is key to understanding the clinical correlates of uncommon serological profiles in SSc.

Published
2016

29. Expert agreement on EULAR/EUSTAR recommendations for the management of systemic sclerosis

Author

Walker, Kyle M., Pope, Janet, Alkassab, F, Molitor, Ja, Shapiro, Ls, Fessler, Bj, Gran, Jt, Goldberg, A, Medsger, TA Jr, VALENTINI, Gabriele, Csuka, Me, Griffing, L, Herrick, A, Connolly, M, Vacca, A, Riemekasten, G, Wigley, Fm, Farge, D, Johnson, Sr, Matucci Cerinic, M, Czirjak, L, Toloza, Sm, Mahmud, Th, Frech, Tm, Voskuyl, Ae, Merkel, Pa, Domsic, R, Emery, P, Steen, V, Rudnicka, L, Denton, Cp, Clements, Pj, Chatterjee, S, Kahaleh, B, Hayat, S, Mouthon, L, Lafyatis, R, Lally, Ev, Krieg, T, Chung, L, Catoggio, Lj, Mayes, Md, Anderson, Me, Silver, R, Proudman, S, Seibold, Jr, Senécal, Jl, Stevens, W, Hachulla, E, Inanc, M, Wollheim, F, Distler, O, Katsumoto, Tr, Hsu, V, Collier, Dh, Furst, D, Mckown, K, Khanna, D, Volkov, S, Mathieu, A, Baron, M, Kaminska, Ea, Khalidi, Na, Hudson, M, Markland, J, Masetto, A, Docherty, P., Walker, Kyle M., Pope, Janet, Alkassab, F, Molitor, Ja, Shapiro, L, Fessler, Bj, Gran, Jt, Goldberg, A, Medsger, TA Jr, Valentini, Gabriele, Csuka, Me, Griffing, L, Herrick, A, Connolly, M, Vacca, A, Riemekasten, G, Wigley, Fm, Farge, D, Johnson, Sr, Matucci Cerinic, M, Czirjak, L, Toloza, Sm, Mahmud, Th, Frech, Tm, Voskuyl, Ae, Merkel, Pa, Domsic, R, Emery, P, Steen, V, Rudnicka, L, Denton, Cp, Clements, Pj, Chatterjee, S, Kahaleh, B, Hayat, S, Mouthon, L, Lafyatis, R, Lally, Ev, Krieg, T, Chung, L, Catoggio, Lj, Mayes, Md, Anderson, Me, Silver, R, Proudman, S, Seibold, Jr, Senécal, Jl, Stevens, W, Hachulla, E, Inanc, M, Wollheim, F, Distler, O, Katsumoto, Tr, Hsu, V, Collier, Dh, Furst, D, Mckown, K, Khanna, D, Volkov, S, Mathieu, A, Baron, M, Kaminska, Ea, Khalidi, Na, Hudson, M, Markland, J, Masetto, A, and Docherty, P.

Subjects
Canada, Scleroderma, Systemic, Hypertension, Pulmonary, Skin Disease, Immunology, Health Survey, Sulfonamide, Epoprostenol, Scleroderma, Europe, Systemic sclerosi, Methotrexate, Treatment Outcome, Rheumatology, North America, Vascular Disease, Practice Guidelines as Topic, Immunology and Allergy, Iloprost, Survey, Societies, Medical, Treatment guideline, Human
Abstract

Objective. The European League Against Rheumatism/EULAR Scleroderma Trials and Research group (EULAR/EUSTAR) has published recommendations for the management of systemic sclerosis (SSc). Members of the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group were surveyed regarding their level of agreement with the recommendations. Methods. A survey containing the 14 EULAR/EUSTAR recommendations asked participants to indicate their level of agreement with each on a 10-point scale, from 0 (not at all) to 9 (completely agree). The survey was sent to 117 people, and 66 replies were received (56% response rate). Results. Exceptions to generally high agreement included the use of iloprost and bosentan for digital vasculopathy, methotrexate for skin involvement, and bosentan and epoprostenol for pulmonary arterial hypertension (PAH; all < 69% agreement, defined as ≥ 7 rating). Vasculopathy and PAH treatment had differences in agreement between North America and Europe (p < 0.006). Respondents who were EULAR/EUSTAR recommendation authors shared a similar level of agreement compared to those who were not, except for the use of proton pump inhibitors for the prevention of SSc-related gastroesophageal reflux disease, esophageal ulcers, and strictures. Conclusion. EULAR/EUSTAR recommendations were relatively well accepted among SSc experts. Overall reduced agreement may be due to the modest efficacy of some agents (such as methotrexate for the skin). Some regional disagreement is likely because of access differences. The Journal of Rheumatology Copyright © 2011. All rights reserved.

Published
2011

30. Reconciling Healthcare Professional and Patient Perspectives in the Development of Disease Activity and Response Criteria in Connective Tissue Disease Related Interstitial Lung Diseases

Author

Saketkoo, La, Mittoo, S, Frankel, S, Lesage, D, Sarver, C, Phillips, K, Strand, V, Matteson, El, OMERACT Baughman RP, Brown, Kk, Christmann, Rb, Dellaripa, P, Denton, Cp, Distler, O, Fischer, A, Flaherty, K, Huscher, D, Khanna, D, Kowal Bielecka, O, Merkel, Pa, Oddis, Cv, Pittrow, D, Sandorfi, N, Seibold, Jr, Swigris, J, Wells, A, Antoniou, K, Castelino, Fv, Christopher Stine, L, Collard, Hr, Cottin, V, Danoff, S, Hedlund, R, Highland, Kb, Hummers, L, Lynch, Da, Kim, Ds, Ryu, Jh, Miller, Fw, Nichols, K, Proudman, Sm, Richeldi, L, Shah, Aa, van den Assum, P, Aggarwal, R, Ainslie, G, Alkassab, F, Allanore, Y, Anderson, Me, Andonopoulos, Ap, Antin Ozerkis, D, Arrobas, A, Ascherman, Dp, Assassi, S, Baron, M, Bathon, Jm, Baughman, Rp, Behr, J, Beretta, L, Bingham, Co, Binnie, M, Birring, Ss, Boin, F, Bongartz, T, Bourdin, A, Bouros, D, Brasington, R, Bresser, P, Buch, Mh, Burge, Ps, Carmona, L, Carreira, Pe, Carvalho, Cr, Catoggio, Lj, Chan, Km, Chapman, J, Chatterjee, S, Chua, F, Chung, L, Conron, M, Corte, T, Cosgrove, G, Costabel, U, Cox, G, Crestani, B, Crofford, Lj, Csuka, Me, Curbelo, P, Czirják, L, Daniil, Z, D'Arsigny, Cl, Davis, Gs, de Andrade JA, Dellaripa, Pf, De Vuyst, P, Dempsey, Oj, Derk, Ct, Distler, J, Dixon, Wg, Downey, G, Doyle, Mk, Drent, M, Durairaj, L, Emery, P, Espinoza, Lr, Farge, D, Fathi, M, Fell, Cd, Fessler, Bj, Fitzgerald, Je, Flaherty, Kr, Foeldvari, I, Fox, Ga, Frech, Tm, Freitas, S, Furst, De, Gabrielli, A, García Vicuña, R, Georgiev, Ob, Gerbino, A, Gillisen, A, Gladman, Dd, Glassberg, M, Gochuico, Br, Gogali, A, Goh, Ns, Goldberg, A, Goldberg, Hj, Gourley, Mf, Griffing, L, Grutters, Jc, Gunnarsson, R, Hachulla, E, Hall, Fc, Harari, S, Herrick, Al, Herzog, El, Hesselstrand, R, Highland, K, Hirani, N, Hodgson, U, Hollingsworth, Hm, Homer, Rj, Hoyles, Rk, Hsu, Vm, Hubbard, Rb, Hunzelmann, N, Isasi, Me, Isasi, Es, Jacobsen, S, Jimenez, Sa, Johnson, Sr, Jones, Ch, Kahaleh, B, Kairalla, Ra, Kalluri, M, Kalra, S, Kaner, Rj, Kinder, Bw, Kiter, G, Klingsberg, Rc, Kokosi, M, Kolb, Mr, Kowal Bielecka OM, Kur Zalewska, J, Kuwana, M, Lake, Fr, Lally, Ev, Lasky, Ja, Laurindo, Im, Able, L, Lee, P, Leonard, Ct, Lien, Dc, Limper, Ah, Liossis, Sn, Lohr, Km, Loyd, Je, Lundberg, Ie, Mageto, Yn, Maher, Tm, Mahmud, Th, Manganas, H, Marie, I, Marras, Tk, Martinez, Ja, Martinez, Fj, Mathieu, A, Matucci Cerinic, M, Mayes, Md, Mckown, Km, Medsger, Ta, Meehan, Rt, Mendes, Ac, Meyer, Kc, Millar, Ab, Moğulkoc, N, Molitor, Ja, Morais, A, Mouthon, L, Müller, V, Müller Quernheim, J, Nadashkevich, O, Nador, R, Nash, P, Nathan, Sd, Navarro, C, Neves, S, Noth, I, Nunes, H, Olson, Al, Opitz, Cf, Padilla, M, Pappas, D, Parfrey, H, Pego Reigosa JM, Pereira, Ca, Perez, R, Pope, Je, Porter, Jc, Renzoni, Ea, Riemekasten, G, Riley, Dj, Rischmueller, M, Rodriguez Reyna TS, Rojas Serrano, J, Roman, J, Rosen, Gd, Rossman, M, Rothfield, N, Sahn, Sa, Sanduzzi, A, Scholand, Mb, Selman, M, Senécal, Jl, Seo, P, Shah, A, Silver, Rm, Solomon, Jj, Steen, V, Stevens, W, Strange, C, Sussman, R, Sutton, Ed, Sweiss, Nj, Tornling, G, Tzelepis, Ge, Undurraga, A, Vacca, A, Vancheri, Carlo, Varga, J, Veale, Dj, Volkov, S, Walker, Ua, Wells, Au, Wencel, M, Wesselius, Lj, Wickremasinghe, M, Wilcox, P, Wilsher, Ml, Wollheim, Fa, Wuyts, Wa, Yung, G, Zanon, P, Zappala, Cj, Groshong, Sd, Leslie, Ko, Myers, Jl, Padera, Rf, Desai, Sr, Goldin, J, Kazerooni, Ea, Klein, Js, and Keen, Kj

Subjects
Male, medicine.medical_specialty, Delphi Technique, Consensus Development Conferences as Topic, Health Personnel, Immunology, Context (language use), Disease, Severity of Illness Index, Article, Idiopathic pulmonary fibrosis, Rheumatology, medicine, Immunology and Allergy, Humans, Disease management (health), Intensive care medicine, Connective Tissue Diseases, Randomized Controlled Trials as Topic, business.industry, Interstitial lung disease, Disease Management, respiratory system, Focus Groups, medicine.disease, Comorbidity, Connective tissue disease, respiratory tract diseases, Clinical trial, Treatment Outcome, Patient Satisfaction, Physical therapy, Quality of Life, ÍNDICE DE GRAVIDADE DA DOENÇA, Interdisciplinary Communication, business, Lung Diseases, Interstitial
Abstract

Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.

Published
2014

31. Identification of IL12RB1 as a novel systemic sclerosis susceptibility locus

Author

López Isac E1, Bossini Castillo, L, Guerra, Sg, Denton, C, Fonseca, C, Assassi, S, Zhou, X, Mayes, Md, Simeón, Cp, Ortego Centeno, N, Castellví, I, Carreira, P, Spanish Scleroderma Group, Gorlova, O, Beretta, L, Santaniello, A, Lunardi, Claudio, Hesselstrand, R, Nordin, A, Riemekasten, G, Witte, T, Hunzelmann, N, Kreuter, A, Distler, Jh, Voskuyl, Ae, de Vries Bouwstra, J, Koeleman, Bp, Herrick, A, Worthington, J, Radstake, Tr, Martin, J., Rheumatology, and CCA - Disease profiling

Subjects
Logistic Models, Scleroderma, Systemic, Gene Frequency, Case-Control Studies, loci, Receptors, Interleukin-12, IL12RB1, Humans, Genetic Predisposition to Disease, Rheumatoid Arthritis, Polymorphism, Single Nucleotide, Article
Published
2014

32. Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: Provisional core sets of domains and instruments for use in clinical trials

Author

Saketkoo, La, Mittoo, S, Huscher, D, Khanna, D, Dellaripa, Pf, Distler, O, Flaherty, Kr, Frankel, S, Oddis, Cv, Denton, Cp, Fischer, A, Kowal Bielecka OM, Lesage, D, Merkel, Pa, Phillips, K, Pittrow, D, Swigris, J, Antoniou, K, Baughman, Rp, Castelino, Fv, Christmann, Rb, Christopher Stine, L, Collard, Hr, Cottin, V, Danoff, S, Highland, Kb, Hummers, L, Shah, Aa, Kim, Ds, Lynch, Da, Miller, Fw, Proudman, Sm, Richeldi, L, Ryu, Jh, Sandorfi, N, Sarver, C, Wells, Au, Strand, V, Matteson, El, Brown, Kk, Seibold, Jr, Aggarwal, R, Ainslie, G, Alkassab, F, Allanore, Y, Descartes, P, Anderson, Me, Andonopoulos, Ap, Antin Ozerkis, D, Arrobas, A, Ascherman, Dp, Assassi, S, Baron, M, Bathon, Jm, Behr, J, Beretta, L, Bingham, Co, Binnie, M, Birring, Ss, Boin, F, Bongartz, T, Bourdin, A, Bouros, D, Brasington, R, Bresser, P, Buch, Mh, Burge, Ps, Carmona, L, Carreira, Pe, Carvalho, Cr, Catoggio, Lj, Chan, Km, Chapman, J, Chatterjee, S, Chua, F, Chung, L, Conron, M, Corte, T, Cosgrove, G, Costabel, U, Cox, G, Crestani, B, Crofford, Lj, Csuka, Me, Curbelo, P, László, C, Daniil, Z, D'Arsigny, Cl, Davis, Gs, de Andrade JA, De Vuyst, P, Dempsey, Oj, Derk, Ct, Distler, J, Dixon, Wg, Downey, G, Doyle, Mk, Drent, M, Durairaj, L, Emery, P, Espinoza, Lr, Farge, D, Fathi, M, Fell, Cd, Fessler, Bj, Fitzgerald, Je, Fox, Ga, Foeldvari, I, Frech, Tm, Freitas, S, Furst, De, Gabrielli, A, García Vicuña, R, Georgiev, Ob, Gerbino, A, Gillisen, A, Gladman, Dd, Glassberg, M, Gochuico, Br, Gogali, A, Goh, Ns, Goldberg, A, Goldberg, Hj, Gourley, Mf, Griffing, L, Grutters, Jc, Gunnarsson, R, Hachulla, E, Hall, Fc, Harari, S, Herrick, Al, Herzog, El, Hesselstrand, R, Hirani, N, Hodgson, U, Hollingsworth, Hm, Homer, Rj, Hoyles, Rk, Hsu, Vm, Hubbard, Rb, Hunzelmann, N, Isasi, Me, Isasi, Es, Jacobsen, S, Jimenez, Sa, Johnson, Sr, Jones, Ch, Kahaleh, B, Kairalla, Ra, Kalluri, M, Kalra, S, Kaner, Rj, Kinder, Bw, Klingsberg, Rc, Kokosi, M, Kolb, Mr, Kur Zalewska, J, Kuwana, M, Lake, Fr, Lally, Ev, Lasky, Ja, Laurindo, Im, Able, L, Lee, P, Leonard, Ct, Lien, Dc, Limper, Ah, Liossis, Sn, Lohr, Km, Loyd, Je, Lundberg, Ie, Mageto, Yn, Maher, Tm, Mahmud, Th, Manganas, H, Marie, I, Marras, Tk, Antônio Baddini Martinez, J, Martinez, Fj, Mathieu, A, Matucci Cerinic, M, Mayes, Md, Mckown, Km, Medsger, Ta, Meehan, Rt, Cristina, Ma, Meyer, Kc, Millar, Ab, Moğulkoc, N, Molitor, Ja, Morais, A, Luc Mouthon, P, Müller, V, Müller Quernheim, J, Nadashkevich, O, Nador, R, Nash, P, Nathan, Sd, Navarro, C, Neves, S, Noth, I, Nunes, H, Olson, Al, Opitz, Cf, Padilla, M, Pappas, D, Parfrey, H, Pego Reigosa JM, Pereira, Ca, Perez, R, Pope, Je, Porter, Jc, Renzoni, Ea, Riemekasten, G, Riley, Dj, Rischmueller, M, Rodriguez Reyna TS, Rojas, Serrano, Roman, J, Rosen, Gd, Rossman, M, Rothfield, N, Sahn, Sa, Sanduzzi, A, Scholand, Mb, Selman, M, Senécal, Jl, Seo, P, Silver, Rm, Solomon, Jj, Steen, V, Stevens, W, Strange, C, Sussman, R, Sutton, Ed, Sweiss, Nj, Tornling, G, Tzelepis, Ge, Undurraga, A, Vacca, A, Vancheri, Carlo, Varga, J, Veale, Dj, Volkov, S, Walker, Ua, Wencel, M, Wesselius, Lj, Wickremasinghe, M, Wilcox, P, Wilsher, Ml, Wollheim, Fa, Wuyts, Wa, Yung, G, Zanon, P, Zappala, Cj, Groshong, Sd, Leslie, Ko, Myers, Jl, Padera, Rf, Desai, Sr, Goldin, J, Kazerooni, Ea, Klein, Js, Cenac, Sl, Grewal, Hk, Christensen, Am, Ferguson, S, Tran, M, Keen, K. J., Costabel, Ulrich (Beitragende*r), Raynauds & Scleroderma Association, Arthritis Research UK, The Scleroderma Society, and British Lung Foundation

Subjects
Lung Diseases, Connective tissue disease associated lung disease, CTD-ILD Special Interest Group, International Cooperation, Respiratory System, Medizin, Rheumatoid lung disease, Idiopathic pulmonary fibrosis, Quality of life, QUALITY-OF-LIFE, CYCLOPHOSPHAMIDE, SCLERODERMA LUNG, Registries, Connective Tissue Diseases, Societies, Medical, Randomized Controlled Trials as Topic, Interstitial lung disease, respiratory system, Connective tissue disease, Interstitial Fibrosis, medicine.anatomical_structure, Life Sciences & Biomedicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Consensus, Clinical Sciences, END-POINT, Interstitial Lung Disease, Systemic disease and lungs, Medical, medicine, Humans, ENSAIO CLÍNICO CONTROLADO RANDOMIZADO, VALIDITY, Intensive care medicine, Lung, Science & Technology, COUGH, business.industry, Clinical study design, MORTALITY, SYSTEMIC-SCLEROSIS, 1103 Clinical Sciences, Congresses as Topic, medicine.disease, GEORGES RESPIRATORY QUESTIONNAIRE, respiratory tract diseases, Clinical trial, IPF, Physical therapy, Interstitial, Societies, business, Lung Diseases, Interstitial
Abstract

Rationale: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods: The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results: A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion: Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

Published
2014

33. Development of a provisional core set of response measures for clinical trials of systemic sclerosis

Author

Khanna D, Lovell DJ, Giannini E, Clements PJ, Merkel PA, Seibold JR, Matucci Cerinic M, Denton CP, Mayes MD, Steen VD, Varga J, Furst DE, Baron M, Csuka ME, Berezne A, Briet SN, Brühlmann P, Buch MH, Catoggio L, Collier D, Crofford L, Czirják L, Derk CT, Distler O, Doyle MK, Farge Bancel D, Fessler B, Foeldvari I, Goldberg A, Gran JT, Grau R, Griffing WL, Hayat S, Herrick AL, Hsu V, Hummers LK, Inanç M, Johnson S, Kahaleh MB, Lafyatis RA, Lee P, Mahmud TH, Malcarne V, McHugh NJ, Martin RW, McKown K, Medsger TA Jr, Moreland L, Pope JE, Rich E, Rothfield NF, Schiopu E, Scorza R, Senécal JL, Shanahan J, Simms RW, Strand V, Silver RM, Sweiss N, van den Hoogen FH, Veale D, Voskuyl AE, Wigley F, Wollheim FA, VALENTINI, Gabriele, Khanna, D, Lovell, Dj, Giannini, E, Clements, Pj, Merkel, Pa, Seibold, Jr, Matucci Cerinic, M, Denton, Cp, Mayes, Md, Steen, Vd, Varga, J, Furst, De, Baron, M, Csuka, Me, Berezne, A, Briet, Sn, Brühlmann, P, Buch, Mh, Catoggio, L, Collier, D, Crofford, L, Czirják, L, Derk, Ct, Distler, O, Doyle, Mk, Farge Bancel, D, Fessler, B, Foeldvari, I, Goldberg, A, Gran, Jt, Grau, R, Griffing, Wl, Hayat, S, Herrick, Al, Hsu, V, Hummers, Lk, Inanç, M, Johnson, S, Kahaleh, Mb, Lafyatis, Ra, Lee, P, Mahmud, Th, Malcarne, V, Mchugh, Nj, Martin, Rw, Mckown, K, Medsger TA, Jr, Moreland, L, Pope, Je, Rich, E, Rothfield, Nf, Schiopu, E, Scorza, R, Senécal, Jl, Shanahan, J, Simms, Rw, Strand, V, Silver, Rm, Sweiss, N, Valentini, Gabriele, van den Hoogen, Fh, Veale, D, Voskuyl, Ae, Wigley, F, and Wollheim, Fa

Subjects
medicine.medical_specialty, Consensus, Delphi Technique, Visual analogue scale, Endpoint Determination, Immunology, Alternative medicine, Delphi method, General Biochemistry, Genetics and Molecular Biology, Article, Rheumatology, Epidemiology, Immunology and Allergy, Medicine, Humans, Multicenter Studies as Topic, computer.programming_language, Core set, Clinical Trials as Topic, Scleroderma, Systemic, business.industry, Outcome measures, Clinical trial, Treatment Outcome, Physical therapy, business, computer, Delphi
Abstract

Objective: To develop a provisional core set of response measures for clinical trials of systemic sclerosis (SSc). Methods: The Scleroderma Clinical Trials Consortium (SCTC) conducted a structured, 3-round Delphi exercise to reach consensus on a core set of measures for clinical trials of SSc. Round 1 asked the SCTC investigators to list items in 11 pre-defined domains (skin, musculoskeletal, cardiac, pulmonary, cardio-pulmonary, gastrointestinal, renal, Raynaud phenomenon and digital ulcers, health-related quality of life and function, global health, and biomarkers) for SSc clinical trials. Round 2 asked respondents to rate the importance of the chosen items and was followed by a meeting, during which the Steering Committee discussed the feasibility, reliability, redundancy and validity of the items. Round 3 sought to obtain broader consensus on the core set measures. Members also voted on items that had data on feasibility but lacked data on reliability and validity, but may still be useful research outcome measures for future trials. Results: A total of 50 SCTC investigators participated in round 1, providing 212 unique items for the 11 domains. In all, 46 (92%) participants responded in round 2 and rated 177 items. The ratings of 177 items were reviewed by the Steering Committee and 31 items from the 11 domains were judged to be appropriate for inclusion in a 1-year multi-centre clinical trial. In total, 40 SCTC investigators completed round 3 and ranked 30 of 31 items as acceptable for inclusion in the core set. The Steering Committee also proposed 14 items for a research agenda. Conclusion: Using a Delphi exercise, we have developed a provisional core set of measures for assessment of disease activity and severity in clinical trials of SSc.

Published
2008

34. Familial aggregation of primary Raynaud's disease

Author

Robert Freedman and Mph Maureen D. Mayes Md

Subjects
Adult, Male, Proband, medicine.medical_specialty, Genetic inheritance, Immunology, Physical examination, Disease, Primary Raynaud's, Rheumatology, Surveys and Questionnaires, Internal medicine, Prevalence, medicine, Humans, Immunology and Allergy, Pharmacology (medical), RAYNAUD DISEASE, Aged, Family Health, medicine.diagnostic_test, Vascular disease, business.industry, Family aggregation, Raynaud Disease, Middle Aged, medicine.disease, Surgery, Female, business
Abstract

Objective. To determine the occurrence of familial aggregation of primary Raynaud's disease. Methods. Twenty-three patients with primary Raynaud's disease and their first-degree relatives were assessed by questionnaire and, when possible, by physical examination. The same procedures were performed on the patients' spouses and the spouses' first-degree relatives, who served as the control group. Results. The prevalence of Raynaud's disease was significantly higher in the families of the probands than in the control families when assessed by questionnaire (26.1% versus 5.5%; P < 10−5), and by physical examination (11.2% versus 2.8%; P = 0.015). Conclusion. These findings demonstrate that there is significant familial aggregation of primary Raynaud's disease.

Published
1996

35. Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis

Author

Diaz-Gallo, LM, primary, Gourh, P, additional, Broen, J, additional, Simeon, C, additional, Fonollosa, V, additional, Ortego-Centeno, N, additional, Agarwal, S, additional, Vonk, MC, additional, Coenen, M, additional, Riemekasten, G, additional, Hunzelmann, N, additional, Hesselstrand, R, additional, Tan, FK, additional, Reveille, JD, additional, Assassi, S, additional, García-Hernandez, FJ, additional, Carreira, P, additional, Camps, MT, additional, Fernandez-Nebro, A, additional, de la Peña, P Garcia, additional, Nearney, T, additional, Hilda, D, additional, González-Gay, MA, additional, Airo, P, additional, Beretta, L, additional, Scorza, R, additional, Herrick, A, additional, Worthington, J, additional, Pros, A, additional, Gómez-Gracia, I, additional, Trapiella, L, additional, Espinosa, G, additional, Castellvi, I, additional, Witte, T, additional, de Keyser, F, additional, Vanthuyne, M, additional, Mayes, MD, additional, Radstake, TRDJ, additional, Arnett, FC, additional, Martin, J, additional, and Rueda, B, additional

Published
2010
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36. Systemic sclerosis and lupus: points in an interferon-mediated continuum.

Author

Assassi S, Mayes MD, Arnett FC, Gourh P, Agarwal SK, McNearney TA, Chaussabel D, Oommen N, Fischbach M, Shah KR, Charles J, Pascual V, Reveille JD, and Tan FK

Abstract

OBJECTIVE: To investigate peripheral blood (PB) cell transcript profiles of systemic sclerosis (SSc) and its subtypes in direct comparison with systemic lupus erythematosus (SLE). METHODS: We investigated PB cell samples from 74 SSc patients, 21 healthy controls, and 17 SLE patients using Illumina Human Ref-8 BeadChips and quantitative polymerase chain reaction confirmation. None of the study participants were receiving immunosuppressive agents other than low-dose steroids and hydroxychloroquine. In addition to conventional statistical and modular analysis, a composite score for the interferon (IFN)-inducible genes was calculated. Within the group of patients with SSc, the correlation of the IFN score with the serologic and clinical subtypes was investigated, as were single-nucleotide polymorphisms in a selected number of IFN pathway genes. RESULTS: Many of the most prominently overexpressed genes in SSc and SLE were IFN-inducible genes. Forty-three of 47 overexpressed IFN-inducible genes in SSc (91%) were similarly altered in SLE. The IFN score was highest in the SLE patients, followed by the SSc patients, and then the controls. The difference in IFN score among all 3 groups was statistically significant (P < 0.001 for all 3 comparisons). SSc and SLE PB cell samples showed striking parallels to our previously reported SSc skin transcripts in regard to the IFN-inducible gene expression pattern. In SSc, the presence of antitopoisomerase and anti-U1 RNP antibodies and lymphopenia correlated with the higher IFN scores (P = 0.005, P = 0.001, and P = 0.004, respectively); a missense mutation in IFNAR2 was significantly associated with the IFN score. CONCLUSION: SLE and SSc fit within the same spectrum of IFN-mediated diseases. A subset of SSc patients shows a 'lupus-like' high IFN-inducible gene expression pattern that correlates with the presence of antitopoisomerase and anti-U1 RNP antibodies. [ABSTRACT FROM AUTHOR]

Published
2010
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37. HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: A genome-wide association study in Koreans with replication in North Americans.

Author

Zhou X, Lee JE, Arnett FC, Xiong M, Park MY, Yoo YK, Shin ES, Reveille JD, Mayes MD, Kim JH, Song R, Choi JY, Park JA, Lee YJ, Lee EY, Song YW, and Lee EB

Abstract

OBJECTIVE: To identify systemic sclerosis (SSc) susceptibility loci via a genome-wide association study. METHODS: A genome-wide association study was performed in 137 patients with SSc and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine-mapping studies, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population. RESULTS: The single-nucleotide polymorphisms (SNPs) (rs3128930, rs7763822, rs7764491, rs3117230, and rs3128965) of HLA-DPB1 and DPB2 on chromosome 6 formed a distinctive peak with log P values for association with SSc susceptibility (P = 8.16 x 10(-13)). Subtyping analysis of HLA-DPB1 showed that DPB1*1301 (P = 7.61 x 10(-8)) and DPB1*0901 (P = 2.55 x 10(-5)) were the subtypes most susceptible to SSc in Korean subjects. In US Caucasians, 2 pairs of SNPs, rs7763822/rs7764491 and rs3117230/rs3128965, showed strong association with SSc patients who had either circulating anti-DNA topoisomerase I (P = 7.58 x 10(-17)/4.84 x 10(-16)) or anticentromere autoantibodies (P = 1.12 x 10(-3)/3.2 x 10(-5)), respectively. CONCLUSION: The results of our genome-wide association study in Korean subjects indicate that the region of HLA-DPB1 and DPB2 contains the loci most susceptible to SSc in a Korean population. The confirmatory studies in US Caucasians indicate that specific SNPs of HLA-DPB1 and/or DPB2 are strongly associated with US Caucasian patients with SSc who are positive for anti-DNA topoisomerase I or anticentromere autoantibodies. [ABSTRACT FROM AUTHOR]

Published
2009
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38. Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: Evidence of possible gene-gene interaction and alterations in Th1/Th2 cytokines.

Author

Gourh P, Agarwal SK, Divecha D, Assassi S, Paz G, Arora-Singh RK, Reveille JD, Shete S, Mayes MD, Arnett FC, and Tan FK

Abstract

OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Dysregulation of the immune system, including the Th1/Th2 cytokine balance, is central to the pathogenesis of SSc. This study was undertaken to investigate the hypothesis that single-nucleotide polymorphisms (SNPs) in TBX21 and STAT4, both of which are critical transcription factors that regulate the Th1/Th2 balance, are associated with SSc susceptibility. METHODS: We tested SNPs in TBX21 and STAT4 for association with SSc in 2 independent cohorts, the SSc Registry cohort (880 SSc cases and 507 controls) and the University of Texas SSc cohort (522 cases and 531 controls). Additional white control genotypes were obtained from public repositories. We also investigated for gene-gene interactions. Plasma cytokines and whole blood gene expression profiles were examined to determine functional effects of these SNPs. RESULTS: Multiple SNPs in TBX21 and STAT4 were found to be associated with SSc. In a combined analysis of 902 SSc patients and 4,745 controls, TT genotyping of the TBX21 rs11650354 variant revealed a recessive pattern for disease susceptibility (P(corr) = 1.4 x 10(-15), odds ratio 3.37, 95% confidence interval 2.4-4.6). In an analysis of 1,039 SSc patients and 3,322 controls, the A allele of the STAT4 variant rs11889341 was associated with increased SSc susceptibility in a dominant pattern (P(corr) = 2.4 x 10(-5), odds ratio 1.29, 95% confidence interval 1.2-1.5). Furthermore, we identified gene-gene interaction among the TBX21 and STAT4 variants, such that the STAT4 genotype increased the risk of SSc only in the TBX21 CC genotype group. SSc patients carrying the TBX21 CC genotype had higher interleukin-6 (IL-6) and tumor necrosis factor alpha levels, and those with the TT genotype had elevated IL-2, IL-5, IL-4, and IL-13 (Th2) levels, compared with controls. Whole blood expression profiles revealed dysregulation of type I interferon pathways in the CC group and T cell pathways in the TT group of the TBX21 SNP. CONCLUSION: The present results, from studies of 2 independent cohorts, indicate that SNPs in TBX21 and STAT4 contribute uniquely and interactively to SSc susceptibility, leading to altered cytokine balance and immune dysregulation. [ABSTRACT FROM AUTHOR]

Published
2009
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39. Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: A randomized, double-blind, placebo-controlled trial.

Author

Khanna D, Clements PJ, Furst DE, Korn JH, Ellman M, Rothfield N, Wigley FM, Moreland LW, Silver R, Kim YH, Steen VD, Firestein GS, Kavanaugh AF, Weisman M, Mayes MD, Collier D, Csuka ME, Simms R, Merkel PA, and Medsger TA Jr

Abstract

OBJECTIVE: A phase II randomized controlled trial of recombinant human relaxin suggested that a dosage of 25 mug/kg/day was safe and clinically effective in improving skin disease and reducing functional disability in scleroderma (systemic sclerosis; SSc). We undertook a large randomized, double-blind, placebo-controlled clinical trial to compare placebo with 10 mug/kg/day and 25 mug/kg/day recombinant human relaxin, given for 24 weeks in patients with stable, diffuse, moderate-to-severe SSc. METHODS: Men and women ages 18-70 years with diffuse cutaneous SSc (dcSSc) were administered recombinant human relaxin (10 mug/kg/day or 25 mug/kg/day) or placebo for 24 weeks as a continuous subcutaneous infusion. There was a followup safety visit at week 28. RESULTS: The primary outcome measure, the modified Rodnan skin thickness score, was similar among the 3 groups at baseline and at weeks 4, 12, and 24. Secondary outcomes such as functional disability were similar in all 3 groups, while the forced vital capacity decreased significantly in the relaxin groups. The discontinuation of both doses of relaxin at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as doubling of serum creatinine, renal crisis, or grade 3 or 4 essential hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo. CONCLUSION: Recombinant relaxin was not significantly better than placebo in improving the total skin score or pulmonary function or in reducing functional disability in patients with dcSSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed. [ABSTRACT FROM AUTHOR]

Published
2009
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41. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part I.

Author

Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH, and National Arthritis Data Workgroup

Abstract

OBJECTIVE: To provide a single source for the best available estimates of the US prevalence of and number of individuals affected by arthritis overall, rheumatoid arthritis, juvenile arthritis, the spondylarthritides, systemic lupus erythematosus, systemic sclerosis, and Sjögren's syndrome. A companion article (part II) addresses additional conditions. METHODS: The National Arthritis Data Workgroup reviewed published analyses from available national surveys, such as the National Health and Nutrition Examination Survey and the National Health Interview Survey (NHIS). For analysis of overall arthritis, we used the NHIS. Because data based on national population samples are unavailable for most specific rheumatic conditions, we derived estimates from published studies of smaller, defined populations. For specific conditions, the best available prevalence estimates were applied to the corresponding 2005 US population estimates from the Census Bureau, to estimate the number affected with each condition. RESULTS: More than 21% of US adults (46.4 million persons) were found to have self-reported doctor-diagnosed arthritis. We estimated that rheumatoid arthritis affects 1.3 million adults (down from the estimate of 2.1 million for 1995), juvenile arthritis affects 294,000 children, spondylarthritides affect from 0.6 million to 2.4 million adults, systemic lupus erythematosus affects from 161,000 to 322,000 adults, systemic sclerosis affects 49,000 adults, and primary Sjögren's syndrome affects from 0.4 million to 3.1 million adults. CONCLUSION: Arthritis and other rheumatic conditions continue to be a large and growing public health problem. Estimates for many specific rheumatic conditions rely on a few, small studies of uncertain generalizability to the US population. This report provides the best available prevalence estimates for the US, but for most specific conditions, more studies generalizable to the US or addressing understudied populations are needed. [ABSTRACT FROM AUTHOR]

Published
2008
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44. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192.

Author

Denton CP, Merkel PA, Furst DE, Khanna D, Emery P, Hsu VM, Silliman N, Streisand J, Powell J, Akesson A, Coppock J, Hoogen F, Herrick A, Mayes MD, Veale D, Haas J, Ledbetter S, Korn JH, Black CM, and Seibold JR

Abstract

OBJECTIVE: To evaluate CAT-192, a recombinant human antibody that neutralizes transforming growth factor beta1 (TGFbeta1), in the treatment of early-stage diffuse cutaneous systemic sclerosis (dcSSc). METHODS: Patients with SSc duration of <18 months were randomly assigned to the placebo group or to 1 of 3 CAT-192 treatment groups: 10 mg/kg, 5 mg/kg, 0.5 mg/kg. Infusions were given on day 0 and weeks 6, 12, and 18. The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of CAT-192. Secondary outcomes included the modified Rodnan skin thickness score (MRSS), the Scleroderma Health Assessment Questionnaire, assessment of organ-based disease, serum levels of soluble interleukin-2 receptor, collagen propeptides (N propeptide of type I [PINP] and type III collagen), and tissue levels of messenger RNA for procollagens I and III and for TGFbeta1 and TGFbeta2. RESULTS: Forty-five patients were enrolled. There was significant morbidity and mortality, including 1 death in the group receiving 0.5 mg/kg of CAT-192 and 3 deaths in the group receiving 5 mg/kg of CAT-192. There were more adverse events and more serious adverse events in patients receiving CAT-192 than in those receiving placebo, although these events were not more frequent in the high-dose treatment group. The MRSS improved in all groups during the study, but there was no evidence of a treatment effect for CAT-192. Improvement in the MRSS correlated with the disease duration (r = -0.54, P = 0.0008). Changes in the PINP level from baseline correlated with changes in the MRSS (r = 0.37, P = 0.027). CONCLUSION: We report the first evaluation of a systemically administered and repeatedly dosed anti-TGFbeta1 drug. In this pilot study, CAT-192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed. [ABSTRACT FROM AUTHOR]

Published
2007
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45. Association of the PTPN22 R620W polymorphism with anti-topoisomerase I- and anticentromere antibody-positive systemic sclerosis.

Author

Gourh P, Tan FK, Assassi S, Ahn CW, McNearney TA, Fischbach M, Arnett FC, and Mayes MD

Subjects
CHROMOSOMES, AUTOANTIBODIES, POPULATION, GENETIC polymorphisms, SYSTEMIC scleroderma, CHOCTAW (North American people), DISEASE susceptibility, ENZYMES, GENOTYPES, ODDS ratio
Abstract

OBJECTIVE: To determine any associations of the PTPN22 R620W single-nucleotide polymorphism (SNP) with systemic sclerosis (SSc) or with anticentromere antibody (ACA)-positive or anti-topoisomerase I (anti-topo I) antibody-positive SSc, in a case-control study of US white, black, Hispanic, and Choctaw Indian individuals. METHODS: A total of 850 white, 130 black, 120 Hispanic, and 20 Choctaw Indian patients with SSc were compared with 430 white, 164 black, 146 Hispanic, and 76 Choctaw Indian control subjects, respectively. All subjects were living in the US. PTPN22 SNP (rs2476601) genotyping was performed by TaqMan 5' allelic discrimination assay and pyrosequencing. RESULTS: The PTPN22 CT/TT genotype showed significant association with anti-topo I antibody-positive SSc in white patients (odds ratio [OR] 2.21, 95% confidence interval [95% CI] 1.3-3.7) and with ACA-positive white patients with SSc (OR 1.70, 95% CI 1.1-2.7). Frequency of the PTPN22*T allele also showed significant association with anti-topo I antibody-positive SSc in white patients (OR 2.03, 95% CI 1.3-3.2). When data for patients in the 3 ethnic groups (black, white, and Hispanic) were combined, a significant association with both genotype and allele frequencies was observed, suggesting a trend toward association in ACA-positive and anti-topo I antibody-positive SSc. Stepwise logistic regression analysis (controlled for the confounding effects of sex and race) showed that the PTPN22 CT/TT genotype was associated with a significantly higher risk of SSc compared with the CC genotype (for patients with SSc, OR 1.64, 95% CI 1.2-2.2; for ACA-positive patients with SSc, OR 1.63, 95% CI 1.0-2.6; for anti-topo I antibody-positive SSc, OR 2.33, 95% CI 1.5-3.7). CONCLUSION: Our results indicate that the PTPN22 R620W polymorphism is associated with ACA-positive and anti-topo I antibody-positive subsets of SSc and represents a risk factor in both white patients and black patients. The association of subsets of SSc with the PTPN22 R620W polymorphism further strengthens the classification of SSc within the spectrum of autoimmune diseases and strongly suggests the involvement of common susceptibility genes and similarly disordered immunoregulatory pathways. [ABSTRACT FROM AUTHOR]

Published
2006
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46. Macrophage migration inhibitory factor promoter polymorphisms and the clinical expression of scleroderma.

Author

Wu SP, Leng L, Feng Z, Liu N, Zhao H, McDonald C, Lee A, Arnett FC, Gregersen PK, Mayes MD, and Bucala R

Abstract

OBJECTIVE: To investigate the potential association between functional polymorphisms in the gene for the innate mediator, macrophage migration inhibitory factor (MIF), and the clinical expression of systemic sclerosis (SSc). METHODS: Genomic DNA samples and clinical data were collected from the Scleroderma Family Registry and DNA Repository at the University of Texas Health Science Center at Houston. A total of 740 subjects were studied; 203 of them had diffuse cutaneous SSc (dcSSc), 283 had limited cutaneous SSc (lcSSc), and the remaining 254 healthy subjects served as controls. Association analyses were performed on the whole data set and on patient and sex subsets. Significant relationships were determined between clinical variables and MIF polymorphisms for each disease subtype in the studied groups. RESULTS: The frequency of the -173*C MIF allele, which was previously reported to be associated with high production of MIF, was lower in the lcSSc group (12.6%) than in the dcSSc (19.2%) or control (18.5%) groups (P = 0.010 and P = 0.011, respectively). Haplotype analysis for 2 closely linked polymorphisms in the MIF promoter showed that in white subjects with lcSSc or dcSSc, the lcSSc population had a significantly lower representation of the high-expression MIF haplotype defined by -173*C and -794 with 7 CATT repeats (C7) (P = 0.015, odds ratio 1.94 [95% confidence interval 1.14-3.32]). Fibroblasts encoding the C7 MIF haplotype were observed to produce more MIF upon in vitro stimulation than those with a non-C7 haplotype. CONCLUSION: Functional promoter polymorphisms in the MIF gene affect the clinical presentation of SSc. The proinflammatory haplotype defined by C7 is underrepresented in patients with lcSSc. [ABSTRACT FROM AUTHOR]

Published
2006

47. Gene profiling of scleroderma skin reveals robust signatures of disease that are imperfectly reflected in the transcript profiles of explanted fibroblasts.

Author

Gardner H, Shearstone JR, Bandaru R, Crowell T, Lynes M, Trojanowska M, Pannu J, Smith E, Jablonska S, Blaszczyk M, Tan FK, and Mayes MD

Abstract

OBJECTIVE: To determine whether biopsy specimens obtained from systemic sclerosis (SSc) lesions show a distinctive gene profile, whether that gene profile is maintained in fibroblasts cultured from SSc skin biopsy specimens, and whether results from tissue obtained from multiple clinical centers can be combined to yield useful observations in this rare disease. METHODS: Biopsy samples and passaged fibroblasts were stored in RNAlater solution prior to processing for RNA. RNA from SSc and control skin biopsy specimens, as well as SSc and control explanted passage 4 fibroblasts, from 9 patients and 9 controls was hybridized to Affymetrix HG-U133A arrays. Data were analyzed using the BRB ArrayTools system. When appropriate, findings were followed up with immunohistochemical analysis or TaqMan studies. RESULTS: Biopsy samples obtained from patients with SSc had a robust and distinctive gene profile, with approximately 1,800 qualifiers distinguishing normal skin from SSc skin at a significant level. The SSc phenotype was the major driver of sample clusters, independent of origin. Alterations in transforming growth factor beta and Wnt pathways, extracellular matrix proteins, and the CCN family were prominent. Explanted fibroblasts from SSc biopsy samples showed a far smaller subset of changes that were relatively variable between samples, suggesting that either nonfibroblast cell types or other aspects of the dermal milieu are required for full expression of the SSc phenotype. CONCLUSION: SSc has a distinct gene profile that is not confounded by geographic location, indicating that extended multicenter studies may be worthwhile to identify distinct subsets of disease by transcript profiling. Explanted SSc fibroblasts show an incomplete reflection of the SSc phenotype. [ABSTRACT FROM AUTHOR]

Published
2006
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48. Risk of malignancy in scleroderma: a population-based cohort study.

Author

Chatterjee S, Dombi GW, Severson RK, and Mayes MD

Abstract

OBJECTIVE: To determine the incidence of cancer in patients with scleroderma (systemic sclerosis) and to compare those rates with cancer rates in the local population. METHODS: Cancer risk in scleroderma patients in the Detroit metropolitan area was assessed by linking patient identification codes of the Michigan Scleroderma Registry to the Metropolitan Detroit Cancer Surveillance System database. Patients were screened between the years 1973 and 2002, with additional followup to 2004. Standardized incidence ratios (SIRs) were calculated for selected malignancies (lung, liver, colon, breast, cervical, and prostate cancers, and non-Hodgkin's lymphomas), with stratification by sex and race. RESULTS: Of 934 patients in the Scleroderma Registry, 538 were included in the study based on tri-county residency (436 females and 102 males). Of these, 45 first malignancies were noted (37 females and 8 males). Lung cancer (10 cases) was found to be the most common cancer in scleroderma patients. However, its incidence was not significantly different from that in the general population of metropolitan Detroit (SIR 1.23). Other types of cancer were examined, and no significant differences were found as compared with the rates in the local population, with 1 exception: black females with scleroderma had significantly higher rates of liver cancer (SIR 45.8). CONCLUSION: Contrary to previous studies, this study did not find statistical evidence of an increased incidence of cancer in scleroderma patients, except for liver cancer. One possible reason is the high background rates of certain cancers in the metropolitan Detroit area. It may be necessary to consider local cancer rates when comparing different scleroderma cohorts. [ABSTRACT FROM AUTHOR]

Published
2005
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50. Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study

Author

Prins, BP, Abbasi, A, Wong, A, Vaez, A, Nolte, I, Franceschini, N, Stuart, PE, Guterriez Achury, J, Mistry, V, Bradfield, JP, Valdes, AM, Bras, J, Shatunov, A, PAGE Consortium, International Stroke Genetics Consortium, Systemic Sclerosis Consortium, Treat OA Consortium, DIAGRAM Consortium, CARDIoGRAMplusC4D Consortium, ALS Consortium, International Parkinson’s Disease Genomics Consortium, Autism Spectrum Disorder Working Group Of The Psychiatric Genomics Consortium, CKDGen Consortium, GERAD1 Consortium, International Consortium For Blood Pressure, Schizophrenia Working Group Of The Psychiatric Genomics Consortium, Inflammation Working Group Of The CHARGE Consortium, Lu, C, Han, B, Raychaudhuri, S, Bevan, S, Mayes, MD, Tsoi, LC, Evangelou, E, Nair, RP, Grant, SFA, Polychronakos, C, Radstake, TRD, Van Heel, DA, Dunstan, ML, Wood, NW, Al-Chalabi, A, Dehghan, A, Hakonarson, H, Markus, HS, Elder, JT, Knight, J, Arking, DE, Spector, TD, Koeleman, BPC, Van Duijn, CM, Martin, J, Morris, AP, Weersma, RK, Wijmenga, C, Munroe, PB, Perry, JRB, Pouget, JG, Jamshidi, Y, Snieder, H, and Alizadeh, BZ

Subjects
C-Reactive Protein, Genotype, Heart Diseases, Immune System Diseases, Metabolic Diseases, Mental Disorders, Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, 3. Good health, Genome-Wide Association Study
Abstract

BACKGROUND: C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. METHODS AND FINDINGS: We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses. CONCLUSIONS: Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes.

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