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1. Disease response in rheumatoid arthritis across four biologic therapies associates with improvement in paraoxonase-1 activity and oxylipins.

Author

Razmjou, Amir, Kremer, Joel, Pappas, Dimitrios, Curtis, Jeffrey, Wang, Jennifer, Shahbazian, Ani, Elashoff, David, Guo, Rong, Meriwether, David, Sulaiman, Dawoud, OConnor, Ellen, Reddy, Srinivasa, and Charles-Schoeman, Christina

Subjects
arthritis, rheumatoid, biological therapy, cardiovascular diseases, Humans, Aryldialkylphosphatase, Arthritis, Rheumatoid, Oxylipins, Female, Male, Middle Aged, Antirheumatic Agents, Biomarkers, Aged, Treatment Outcome, Adult, Antibodies, Monoclonal, Humanized, Biological Therapy, Rituximab, Severity of Illness Index, Abatacept, Tumor Necrosis Factor Inhibitors
Abstract

OBJECTIVE: Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme, that has been implicated as a biomarker of cardiovascular risk in patients with rheumatoid arthritis (RA). We aimed to investigate how different biologic therapies affect levels of PON1 and oxylipins. METHODS: 1213 adult patients with RA in the Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory CoNditions cohort study with moderate-to-high disease activity (Clinical Disease Activity Index (CDAI) >10) who initiated a new biologic (tocilizumab (TCZ), n=296; abatacept, n=374; tumour necrosis factor inhibitors, n=427; rituximab, n=116) were followed prospectively with serum specimens analysed for PON1 activity by arylesterase (ARYL), lactonase (LAC) and PON assays at baseline and after 6 months of biologic therapy. A targeted panel of oxylipins was evaluated by liquid chromatography-mass spectrometry/mass spectrometry in a subset of patients with the lowest and highest 6-month Disease Activity Score 28 (DAS28)-C reactive protein (CRP) responses in each treatment group. RESULTS: PON1 activity generally increased in the entire cohort after 6 months of new biologic therapy, showing the greatest, most consistent increases in the TCZ group. Increases in all three PON1 domains associated with significant decreases in disease activity in DAS28-CRP/CDAI (p

Published
2024

11. Energy and emissions accounting : the case of intra-regional industrial shifts in SE Asia

Author

Pappas, Dimitrios

Abstract

The potential relocation of various industrial sectors from China to India and countries of the SE Asian region presents low cost opportunities for manufacturers, but also risks are rising for energy demand and CO2 emissions. A cross-country shift of industrial output presents challenges in accounting, controlling, and defining energy and emissions requirements. This is pronounced for the case of India and SE Asian countries as they experience high economic growth rates, by global standards, and strong coupling between economic growth and energy demand. This thesis locates the existing emissions accounting gaps of India, which acts as a potential host of the Chinese manufacturing activities. It concludes that significant differences are present in the majority of the industrial sectors studied. Indian emissions intensity is double that of China in the iron and steel and triple for the cement industry. The decomposition of selected CO2 drivers exemplifies the added significance of labour productivity and industrial scale in driving industrial emissions. Fuel mix concentration in industrial activities is found to be a requirement for every potential host country, highlighting an urgency for diversification if production is to be sustainable. The results demonstrated by this thesis, show that reporting authorities must reach a methodological consensus for increased efficiency in carbon emissions future policy. Carbon emissions are driven by higher carbon fuel mix intensity in the host countries and higher energy intensity in their industrial activities. This thesis effectively concludes that while industrial relocation could further benefit the host countries in financial terms, it would impose considerable threats to their energy supply security and compliance capacity, with the environmental commitments set by the Paris Agreement.

Published
2019

16. A Molecular Signature Response Classifier to Predict Inadequate Response to Tumor Necrosis Factor-α Inhibitors: The NETWORK-004 Prospective Observational Study

Author

Cohen, Stanley, Wells, Alvin F., Curtis, Jeffrey R., Dhar, Rajat, Mellors, Theodore, Zhang, Lixia, Withers, Johanna B., Jones, Alex, Ghiassian, Susan D., Wang, Mengran, Connolly-Strong, Erin, Rapisardo, Sarah, Gatalica, Zoran, Pappas, Dimitrios A., Kremer, Joel M., Saleh, Alif, and Akmaev, Viatcheslav R.

Published
2021
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18. Prevalence of Fibromyalgia and Widespread Pain in Psoriatic Arthritis: Association With Disease Severity Assessment in a Large US Registry.

Author

Mease, Philip, Reed, George, Ogdie, Alexis, Pappas, Dimitrios A., and Kremer, Joel M.

Subjects
ETIOLOGY of diseases, PSORIATIC arthritis, BODY mass index, PAIN measurement, NERVE fibers, FIBROMYALGIA
Abstract

Objective: The classic conception of pain etiology in rheumatologic disease is nociceptive pain—tissue injury and inflammation signaling through peripheral and central nerve fibers. But this can be mixed with other pain etiologies, including nociplastic, which is augmented pain experience due to central sensitization. The pain of fibromyalgia (FM) is nociplastic, occurs in 10% to 30% of patients with rheumatologic disease, and its presence can influence disease severity assessment. The objective of our study was to (1) ascertain the prevalence of FM and widespread pain (WP) in the CorEvitas psoriatic arthritis (PsA) registry as assessed by the Widespread Pain Index (WPI) and Symptom Severity Scale (SSS) questionnaires; (2) characterize the demographic and clinical factors associated with FM and WP; and (3) ascertain the association of FM and WP on the Clinical Disease Activity in Psoriatic Arthritis (cDAPSA) score and other disease activity measures. Methods: PsA registry patients completing the WPI/SSS questionnaires since May 2020, at their most recent visit recorded in the registry, were analyzed. Results: The analysis included 1,823 patients with PsA; 11.1% fulfilled the FM definition and 20.6% fulfilled the WP definition. Several factors were associated with the FM definition, including female sex, depression and/or anxiety, impaired function, increased body mass index, and increased number of comorbidities. cDAPSA, patient pain and global assessment, and tender joint count were twice as severe in patients with FM compared to those without. Conclusion: FM prevalence is elevated in PsA and is associated with elevated disease measures, confounding reliable disease assessment for treat‐to‐target goals. Identification of FM as an influential contextual factor in disease assessment is recommended. [ABSTRACT FROM AUTHOR]

Published
2024
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28. An improved method for the computation of the Moore-Penrose inverse matrix

Author

Katsikis, Vasilios N., Pappas, Dimitrios, and Petralias, Athanassios

Subjects
Mathematics - Numerical Analysis, 15A09
Abstract

In this article we provide a fast computational method in order to calculate the Moore-Penrose inverse of singular square matrices and of rectangular matrices. The proposed method proves to be much faster and has significantly better accuracy than the already proposed methods, while works for full and sparse matrices., Comment: 11 pages, 1 figure

Published
2011

29. Restricted Linear Constrained Minimization of quadratic functionals

Author

Pappas, Dimitrios

Subjects
Mathematics - Optimization and Control, 47A05, 47N10, 15A09
Abstract

In this work a linearly constrained minimization of a positive semidefinite quadratic functional is examined. Our results are concerning infinite dimensional real Hilbert spaces, with a singular positive operator related to the functional, and considering as constraint a singular operator. The difference between the proposed minimization and previous work on this problem, is that it is considered for all vectors perpendicular to the kernel of the related operator or matrix., Comment: 14 pages, 2 figures

Published
2010

30. Minimization of Constrained Quadratic forms in Hilbert Spaces

Author

Pappas, Dimitrios

Subjects
Mathematics - Functional Analysis, 47A05, 47N10, 15A09.
Abstract

A common optimization problem is the minimization of a symmetric positive definite quadratic form $< x,Tx >$ under linear constrains. The solution to this problem may be given using the Moore-Penrose inverse matrix. In this work we extend this result to infinite dimensional complex Hilbert spaces, making use of the generalized inverse of an operator. A generalization is given for positive diagonizable and arbitrary positive operators, not necessarily invertible, considering as constraint a singular operator. In particular, when $T$ is positive semidefinite, the minimization is considered for all vectors belonging to $\mathcal{N}(T)^\perp$., Comment: 17 pages, 2 figures

Published
2010

33. Factorizations of EP operators

Author

Drivaliaris, Dimosthenis, Karanasios, Sotirios, and Pappas, Dimitrios

Subjects
Mathematics - Functional Analysis, Mathematics - Rings and Algebras, 47A05 (Primary) 15A09, 47B (Secondary)
Abstract

In this paper we characterize EP operators through the existence of different types of factorizations. Our results extend to EP operators existing characterizations for EP matrices and give new characterizations both for EP matrices and EP operators., Comment: To appear in Linear Algebra and its Applications

Published
2008

38. Genetics of rheumatoid arthritis contributes to biology and drug discovery.

Author

Okada, Yukinori, Wu, Di, Trynka, Gosia, Raj, Towfique, Terao, Chikashi, Ikari, Katsunori, Kochi, Yuta, Ohmura, Koichiro, Suzuki, Akari, Yoshida, Shinji, Graham, Robert, Manoharan, Arun, Ortmann, Ward, Bhangale, Tushar, Denny, Joshua, Carroll, Robert, Eyler, Anne, Greenberg, Jeffrey, Kremer, Joel, Pappas, Dimitrios, Jiang, Lei, Yin, Jian, Ye, Lingying, Su, Ding-Feng, Yang, Jian, Xie, Gang, Keystone, Ed, Westra, Harm-Jan, Esko, Tõnu, Metspalu, Andres, Zhou, Xuezhong, Gupta, Namrata, Mirel, Daniel, Stahl, Eli, Diogo, Dorothée, Cui, Jing, Liao, Katherine, Guo, Michael, Myouzen, Keiko, Kawaguchi, Takahisa, Coenen, Marieke, van Riel, Piet, van de Laar, Mart, Guchelaar, Henk-Jan, Huizinga, Tom, Dieudé, Philippe, Mariette, Xavier, Bridges, S, Zhernakova, Alexandra, Toes, Rene, Tak, Paul, Miceli-Richard, Corinne, Bang, So-Young, Lee, Hye-Soon, Martin, Javier, Gonzalez-Gay, Miguel, Rodriguez-Rodriguez, Luis, Rantapää-Dahlqvist, Solbritt, Arlestig, Lisbeth, Choi, Hyon, Kamatani, Yoichiro, Galan, Pilar, Lathrop, Mark, Eyre, Steve, Bowes, John, Barton, Anne, de Vries, Niek, Moreland, Larry, Karlson, Elizabeth, Taniguchi, Atsuo, Yamada, Ryo, Kubo, Michiaki, Liu, Jun, Bae, Sang-Cheol, Worthington, Jane, Padyukov, Leonid, Klareskog, Lars, Gregersen, Peter, Raychaudhuri, Soumya, Stranger, Barbara, De Jager, Philip, Franke, Lude, Visscher, Peter, Brown, Matthew, Yamanaka, Hisashi, Mimori, Tsuneyo, Takahashi, Atsushi, Xu, Huji, Behrens, Timothy, Siminovitch, Katherine, Momohara, Shigeki, Matsuda, Fumihiko, Yamamoto, Kazuhiko, Plenge, Robert, and Criswell, Lindsey

Subjects
Alleles, Animals, Arthritis, Rheumatoid, Asian People, Case-Control Studies, Computational Biology, Drug Discovery, Drug Repositioning, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Hematologic Neoplasms, Humans, Male, Mice, Mice, Knockout, Molecular Targeted Therapy, Polymorphism, Single Nucleotide, White People
Abstract

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Published
2014

45. Prevalence of cardiovascular disease and major risk factors in patients with rheumatoid arthritis: a multinational cross-sectional study

Author

Pappas, Dimitrios A., Nyberg, Fredrik, Kremer, Joel M., Lampl, Kathy, Reed, George W., Horne, Laura, Ho, Meilien, Onofrei, Alina, Malaviya, Anand N., Rillo, Oscar L., Radominski, Sebastiao C., Gal, Janos, Gibofsky, Allan, Popkova, Tatiana V., Laurindo, Leda, Kerzberg, Eduardo M., Zahora, Roman, Pons-Estel, Bernado A., Curtis, Jeffrey R., Furst, Daniel E., and Greenberg, Jeffrey D.

Published
2018
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48. Molecular profiling of rheumatoid arthritis patients reveals an association between innate and adaptive cell populations and response to anti-tumor necrosis factor

Author

Farutin, Victor, Prod’homme, Thomas, McConnell, Kevin, Washburn, Nathaniel, Halvey, Patrick, Etzel, Carol J., Guess, Jamey, Duffner, Jay, Getchell, Kristen, Meccariello, Robin, Gutierrez, Bryan, Honan, Christopher, Zhao, Ganlin, Cilfone, Nicholas A., Gunay, Nur Sibel, Hillson, Jan L., DeLuca, David S., Saunders, Katherine C., Pappas, Dimitrios A., Greenberg, Jeffrey D., Kremer, Joel M., Manning, Anthony M., Ling, Leona E., and Capila, Ishan

Published
2019
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49. Anti-citrullinated protein antibody profiles predict changes in disease activity in patients with rheumatoid arthritis initiating biologics.

Author

Aripova, Nozima, Kremer, Joel M, Pappas, Dimitrios A, Reed, George, England, Bryant R, Robinson, Bill H, Curtis, Jeffrey R, Thiele, Geoffrey M, and Mikuls, Ted R

Subjects
BIOTHERAPY, AUTOANTIBODIES, DRUG efficacy, STATISTICS, SCIENTIFIC observation, CONFIDENCE intervals, ANTI-inflammatory agents, MULTIVARIATE analysis, HEALTH outcome assessment, REGRESSION analysis, TREATMENT effectiveness, RHEUMATOID arthritis, FACTOR analysis, DESCRIPTIVE statistics, RESEARCH funding, ODDS ratio, LONGITUDINAL method, ABATACEPT
Abstract

Objectives To determine whether an expanded antigen-specific ACPA profile predicts changes in disease activity in patients with RA initiating biologics. Methods The study included participants from a prospective, non-randomized, observational RA cohort. For this sub-study, treatment groups of interest included biologic-naïve initiating anti-TNF, biologic-exposed initiating non-TNF, and biologic-naïve initiating abatacept. ACPAs to 25 citrullinated peptides were measured using banked enrolment serum. Principal component analysis (PCA) was performed and associations of resulting principal component (PC) scores (in quartiles) and anti-CCP3 antibody (≤15, 16–250 or >250 U/ml) with EULAR (good/moderate/none) treatment response at 6 months were examined using adjusted ordinal regression models. Results Participants (n  = 1092) had a mean age of 57 (13) years and 79% were women. At 6 months, 68.5% achieved a moderate/good EULAR response. There were three PCs that cumulatively explained 70% of variation in ACPA values. In models including the three components and anti-CCP3 antibody category, only PC1 and PC2 were associated with treatment response. The highest quartile for PC1 (odds ratio [OR] 1.76; 95% CI: 1.22, 2.53) and for PC2 (OR 1.74; 95% CI: 1.23, 2.46) were associated with treatment response after multivariable adjustment. There was no evidence of interaction between PCs and treatment group in EULAR responses (P -value for interaction >0.1). Conclusion An expanded ACPA profile appears to be more strongly associated with biologic treatment response in RA than commercially available anti-CCP3 antibody levels. However, further enhancements to PCA will be needed to effectively prioritize between different biologics available for the treatment of RA. [ABSTRACT FROM AUTHOR]

Published
2024
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