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1. Whole body insulin sensitivity is increased in systemic sclerosis.

Author

Jacopo Ciaffi, Piero Ruscitti, Ilenia Di Cola, Viktoriya Pavlych, Noemi Italiano, Martina Gentile, Tom Huizinga, Jeska K de Vries-Bouwstra, Francesco Ursini, and Paola Cipriani

Subjects
Medicine, Science
Abstract

ObjectivesIn the present study, we aimed to evaluate whole-body insulin sensitivity in systemic sclerosis (SSc) patients and to compare the results with controls with no autoimmune rheumatic disease (non-ARD) and with patients affected by rheumatoid arthritis (RA).MethodsIn all patients and controls, oral glucose tolerance test (OGTT) was performed according to the World Health Organization (WHO) recommendations. Plasma glucose and insulin concentrations were measured at time 0 and then after 30, 60, 90, and 120 minutes. Whole-body insulin sensitivity (ISI), insulinogenic index (IGI), oral disposition index (ODI), and insulin resistance (HOMA-IR) were estimated accordingly.ResultsA total of 41 SSc patients were evaluated and, for comparison, 41 individuals with RA and 82 non-ARD control patients were recruited. OGTT yielded a proportion of normotolerant individuals among SSc patients higher than in RA controls (p = 0.040) but lower than in the non-ARD group (p = 0.028). The ISI was significantly higher in SSc patients compared with RA controls (p ConclusionsInterestingly, we found that SSc patients are more insulin sensitive than those with RA and even than individuals without inflammatory diseases. In contrast, no significant difference was found in terms of β-cell function.

Published
2023
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2. Rheumatic?—A Digital Diagnostic Decision Support Tool for Individuals Suspecting Rheumatic Diseases: A Multicenter Pilot Validation Study

Author

Rachel Knevel, Johannes Knitza, Aase Hensvold, Alexandra Circiumaru, Tor Bruce, Sebastian Evans, Tjardo Maarseveen, Marc Maurits, Liesbeth Beaart-van de Voorde, David Simon, Arnd Kleyer, Martina Johannesson, Georg Schett, Tom Huizinga, Sofia Svanteson, Alexandra Lindfors, Lars Klareskog, and Anca Catrina

Subjects
eHealth, symptom assessment, diagnostics, rheumatology, mHealth (mobile health), Medicine (General), R5-920
Abstract

IntroductionDigital diagnostic decision support tools promise to accelerate diagnosis and increase health care efficiency in rheumatology. Rheumatic? is an online tool developed by specialists in rheumatology and general medicine together with patients and patient organizations. It calculates a risk score for several rheumatic diseases. We ran a pilot study retrospectively testing Rheumatic? for its ability to differentiate symptoms from existing or emerging immune-mediated rheumatic diseases from other rheumatic and musculoskeletal complaints and disorders in patients visiting rheumatology clinics.Materials and MethodsThe performance of Rheumatic? was tested using in three university rheumatology centers: (A) patients at Risk for RA (Karolinska Institutet, n = 50 individuals with musculoskeletal complaints and anti-citrullinated protein antibody positivity) (B) patients with early joint swelling [dataset B (Erlangen) n = 52]. (C) Patients with early arthritis where the clinician considered it likely to be of auto-immune origin [dataset C (Leiden) n = 73]. In dataset A we tested whether Rheumatic? could predict the development of arthritis. In dataset B and C we tested whether Rheumatic? could predict the development of an immune-mediated rheumatic diseases. We examined the discriminative power of the total score with the Wilcoxon rank test and the area-under-the-receiver-operating-characteristic curve (AUC-ROC). Next, we calculated the test characteristics for these patients passing the first or second expert-based Rheumatic? scoring threshold.ResultsThe total test scores differentiated between: (A) Individuals developing arthritis or not, median 245 vs. 163, P < 0.0001, AUC-ROC = 75.3; (B) patients with an immune-mediated arthritic disease or not median 191 vs. 107, P < 0.0001, AUC-ROC = 79.0; but less patients with an immune-mediated arthritic disease or not amongst those where the clinician already considered an immune mediated disease most likely (median 262 vs. 212, P < 0.0001, AUC-ROC = 53.6). Threshold-1 (advising to visit primary care doctor) was highly specific in dataset A and B (0.72, 0.87, and 0.23, respectively) and sensitive (0.67, 0.61, and 0.67). Threshold-2 (advising to visit rheumatologic care) was very specific in all three centers but not very sensitive: specificity of 1.0, 0.96, and 0.91, sensitivity 0.05, 0.07, 0.14 in dataset A, B, and C, respectively.ConclusionRheumatic? is a web-based patient-centered multilingual diagnostic tool capable of differentiating immune-mediated rheumatic conditions from other musculoskeletal problems. The current scoring system needs to be further optimized.

Published
2022
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3. New risk model is able to identify patients with a low risk of progression in systemic sclerosis

Author

Jeska De Vries-Bouwstra, Tom Huizinga, Cornelia Allaart, Jacopo Ciaffi, Robbert Goekoop, Nina Marijn van Leeuwen, Marc Maurits, Sophie Liem, Maarten Ninaber, and Henrike Gillet van Dongen

Subjects
Medicine
Abstract

Objectives To develop a prediction model to guide annual assessment of systemic sclerosis (SSc) patients tailored in accordance to disease activity.Methods A machine learning approach was used to develop a model that can identify patients without disease progression. SSc patients included in the prospective Leiden SSc cohort and fulfilling the ACR/EULAR 2013 criteria were included. Disease progression was defined as progression in ≥1 organ system, and/or start of immunosuppression or death. Using elastic-net-regularisation, and including 90 independent clinical variables (100% complete), we trained the model on 75% and validated it on 25% of the patients, optimising on negative predictive value (NPV) to minimise the likelihood of missing progression. Probability cutoffs were identified for low and high risk for disease progression by expert assessment.Results Of the 492 SSc patients (follow-up range: 2–10 years), disease progression during follow-up was observed in 52% (median time 4.9 years). Performance of the model in the test set showed an AUC-ROC of 0.66. Probability score cutoffs were defined: low risk for disease progression (0.223, NPV:0.78; 44%). The relevant variables for the model were: previous use of cyclophosphamide or corticosteroids, start with immunosuppressive drugs, previous gastrointestinal progression, previous cardiovascular event, pulmonary arterial hypertension, modified Rodnan Skin Score, creatine kinase and diffusing capacity for carbon monoxide.Conclusion Our machine-learning-assisted model for progression enabled us to classify 29% of SSc patients as ‘low risk’. In this group, annual assessment programmes could be less extensive than indicated by international guidelines.

Published
2021
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4. Quantitative susceptibility mapping in the thalamus and basal ganglia of systemic lupus erythematosus patients with neuropsychiatric complaints

Author

Marjolein Bulk, Thijs van Harten, Boyd Kenkhuis, Francesca Inglese, Ingrid Hegeman, Sjoerd van Duinen, Ece Ercan, César Magro-Checa, Jelle Goeman, Christian Mawrin, Mark van Buchem, Gerda Steup-Beekman, Tom Huizinga, Louise van der Weerd, and Itamar Ronen

Subjects
Quantitative susceptibility mapping, Neuropsychiatric systemic lupus erythematosus, Neuroinflammation, Basal ganglia, Iron accumulation, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Systemic lupus erythematosus (SLE) is an auto-immune disease characterized by multi-organ involvement. Although uncommon, central nervous system involvement in SLE, termed neuropsychiatric SLE (NPSLE), is not an exception. Current knowledge on underlying pathogenic mechanisms is incomplete, however, neuroinflammation is thought to play a critical role. Evidence from neurodegenerative diseases and multiple sclerosis suggests that neuroinflammation is correlated with brain iron accumulation, making quantitative susceptibility mapping (QSM) a potential hallmark for neuroinflammation in vivo. This study assessed susceptibility values of the thalamus and basal ganglia in (NP)SLE patients and further investigated the in vivo findings with histological analyses of postmortem brain tissue derived from SLE patients. We used a 3T MRI scanner to acquire single-echo T2*-weighted images of 44 SLE patients and 20 age-matched healthy controls. Of the 44 patients with SLE, all had neuropsychiatric complaints, of which 29 were classified as non-NPSLE and 15 as NPSLE (seven as inflammatory NPSLE and eight as ischemic NPSLE). Mean susceptibility values of the thalamus, caudate nucleus, putamen, and globus pallidus were calculated. Formalin-fixed paraffin-embedded post-mortem brain tissue including the putamen and globus pallidus of three additional SLE patients was obtained and stained for iron, microglia and astrocytes. Susceptibility values of SLE patients and age-matched controls showed that iron levels in the thalamus and basal ganglia were not changed due to the disease. No subgroup of SLE showed higher susceptibility values. No correlation was found with disease activity or damage due to SLE. Histological examination of the post-mortem brain showed no increased iron accumulation. Our results suggest that neuroinflammation in NPSLE does not necessarily go hand in hand with iron accumulation, and that the inflammatory pathomechanism in SLE may differ from the one observed in neurodegenerative diseases and in multiple sclerosis.

Published
2021
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5. Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

Author

Signe Hässler, Delphine Bachelet, Julianne Duhaze, Natacha Szely, Aude Gleizes, Salima Hacein-Bey Abina, Orhan Aktas, Michael Auer, Jerôme Avouac, Mary Birchler, Yoram Bouhnik, Olivier Brocq, Dorothea Buck-Martin, Guillaume Cadiot, Franck Carbonnel, Yehuda Chowers, Manuel Comabella, Tobias Derfuss, Niek De Vries, Naoimh Donnellan, Abiba Doukani, Michael Guger, Hans-Peter Hartung, Eva Kubala Havrdova, Bernhard Hemmer, Tom Huizinga, Kathleen Ingenhoven, Poul Erik Hyldgaard-Jensen, Elizabeth C Jury, Michael Khalil, Bernd Kieseier, Anna Laurén, Raija Lindberg, Amy Loercher, Enrico Maggi, Jessica Manson, Claudia Mauri, Badreddine Mohand Oumoussa, Xavier Montalban, Maria Nachury, Petra Nytrova, Christophe Richez, Malin Ryner, Finn Sellebjerg, Claudia Sievers, Dan Sikkema, Martin Soubrier, Sophie Tourdot, Caroline Trang, Alessandra Vultaggio, Clemens Warnke, Sebastian Spindeldreher, Pierre Dönnes, Timothy P Hickling, Agnès Hincelin Mery, Matthieu Allez, Florian Deisenhammer, Anna Fogdell-Hahn, Xavier Mariette, Marc Pallardy, Philippe Broët, and ABIRISK consortium

Subjects
Medicine
Abstract

BackgroundBiopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited.Methods and findingsThe European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings.ConclusionIn our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.

Published
2020
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6. Induction of sustained remission in early inflammatory arthritis with the combination of infliximab plus methotrexate: the DINORA trial

Author

Tanja Alexandra Stamm, Klaus Peter Machold, Daniel Aletaha, Farideh Alasti, Peter Lipsky, David Pisetsky, Robert Landewe, Desiree van der Heijde, Alexandre Sepriano, Martin Aringer, Dimitri Boumpas, Gerd Burmester, Maurizio Cutolo, Wolfgang Ebner, Winfried Graninger, Tom Huizinga, Georg Schett, Hendrik Schulze-Koops, Paul-Peter Tak, Emilio Martin-Mola, Ferdinand Breedveld, and Josef Smolen

Subjects
Clinical remission, Early arthritis, Rheumatoid arthritis, Diseases of the musculoskeletal system, RC925-935
Abstract

Abstract Background In the present study, we explored the effects of immediate induction therapy with the anti-tumour necrosis factor (TNF)α antibody infliximab (IFX) plus methotrexate (MTX) compared with MTX alone and with placebo (PL) in patients with very early inflammatory arthritis. Methods In an investigator-initiated, double-blind, randomised, placebo-controlled, multi-centre trial (ISRCTN21272423, http://www.isrctn.com/ISRCTN21272423), patients with synovitis of 12 weeks duration in at least two joints underwent 1 year of treatment with IFX in combination with MTX, MTX monotherapy, or PL randomised in a 2:2:1 ratio. The primary endpoint was clinical remission after 1 year (sustained for at least two consecutive visits 8 weeks apart) with remission defined as no swollen joints, 0–2 tender joints, and an acute-phase reactant within the normal range. Results Ninety patients participated in the present study. At week 54 (primary endpoint), 32% of the patients in the IFX + MTX group achieved sustained remission compared with 14% on MTX alone and 0% on PL. This difference (p

Published
2018
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7. A multimodal MRI approach to identify and characterize microstructural brain changes in neuropsychiatric systemic lupus erythematosus

Author

Ece Ercan, Carson Ingo, Oranan Tritanon, Cesar Magro-Checa, Alex Smith, Seth Smith, Tom Huizinga, Mark A. van Buchem, and Itamar Ronen

Subjects
Systemic lupus erythematosus, Neuropsychiatric systemic lupus erythematosus, Magnetic resonance imaging, Diffusion tensor imaging, Magnetization transfer imaging, Normal appearing white matter, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement and results in neurological and psychiatric (NP) symptoms in up to 40% of the patients. To date, the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) poses a challenge due to the lack of neuroradiological gold standards. In this study, we aimed to better localize and characterize normal appearing white matter (NAWM) changes in NPSLE by combining data from two quantitative MRI techniques, diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI). 9 active NPSLE patients (37 ± 13 years, all females), 9 SLE patients without NP symptoms (44 ± 11 years, all females), and 14 healthy controls (HC) (40 ± 9 years, all females) were included in the study. MTI, DTI and fluid attenuated inversion recovery (FLAIR) images were collected from all subjects on a 3 T MRI scanner. Magnetization transfer ratio (MTR), mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) maps and white matter lesion maps based on the FLAIR images were created for each subject. MTR and DTI data were then co-analyzed using tract-based spatial statistics and a cumulative lesion map to exclude lesions. Significantly lower MTR and FA and significantly higher AD, RD and MD were found in NPSLE compared to HC in NAWM regions. The differences in DTI measures and in MTR, however, were only moderately co-localized. Additionally, significant differences in DTI measures, but not in MTR, were found between NPSLE and SLE patients, suggesting that the underlying microstructural changes detected by MD are linked to the onset of NPSLE. The co-analysis of the anatomical distribution of MTI and DTI measures can potentially improve the diagnosis of NPSLE and contribute to the understanding of the underlying microstructural damage.

Published
2015
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8. Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis

Author

Kazuyoshi, Ishigaki, Saori, Sakaue, Chikashi, Terao, Yang, Luo, Kyuto, Sonehara, Kensuke, Yamaguchi, Tiffany, Amariuta, Chun Lai, Too, Vincent A, Laufer, Ian C, Scott, Sebastien, Viatte, Meiko, Takahashi, Koichiro, Ohmura, Akira, Murasawa, Motomu, Hashimoto, Hiromu, Ito, Mohammed, Hammoudeh, Samar Al, Emadi, Basel K, Masri, Hussein, Halabi, Humeira, Badsha, Imad W, Uthman, Xin, Wu, Li, Lin, Ting, Li, Darren, Plant, Anne, Barton, Gisela, Orozco, Suzanne M M, Verstappen, John, Bowes, Alexander J, MacGregor, Suguru, Honda, Masaru, Koido, Kohei, Tomizuka, Yoichiro, Kamatani, Hiroaki, Tanaka, Eiichi, Tanaka, Akari, Suzuki, Yuichi, Maeda, Kenichi, Yamamoto, Satoru, Miyawaki, Gang, Xie, Jinyi, Zhang, Christopher I, Amos, Edward, Keystone, Gertjan, Wolbink, Irene, van der Horst-Bruinsma, Jing, Cui, Katherine P, Liao, Robert J, Carroll, Hye-Soon, Lee, So-Young, Bang, Katherine A, Siminovitch, Niek, de Vries, Lars, Alfredsson, Solbritt, Rantapää-Dahlqvist, Elizabeth W, Karlson, Sang-Cheol, Bae, Robert P, Kimberly, Jeffrey C, Edberg, Xavier, Mariette, Tom, Huizinga, Philippe, Dieudé, Matthias, Schneider, Martin, Kerick, Joshua C, Denny, Koichi, Matsuda, Keitaro, Matsuo, Tsuneyo, Mimori, Fumihiko, Matsuda, Keishi, Fujio, Yoshiya, Tanaka, Atsushi, Kumanogoh, Matthew, Traylor, Cathryn M, Lewis, Stephen, Eyre, Huji, Xu, Richa, Saxena, Thurayya, Arayssi, Yuta, Kochi, Katsunori, Ikari, Masayoshi, Harigai, Peter K, Gregersen, Kazuhiko, Yamamoto, S, Louis Bridges, Leonid, Padyukov, Javier, Martin, Lars, Klareskog, Yukinori, Okada, Soumya, Raychaudhuri, AII - Inflammatory diseases, Experimental Immunology, Clinical Immunology and Rheumatology, Rheumatology, AMS - Musculoskeletal Health, and AMS - Tissue Function & Regeneration

Subjects
Arthritis, Rheumatoid, Asian People, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study, Adaptor Proteins, Signal Transducing
Abstract

Multi-ancestry genome-wide association analyses identify 124 risk loci for rheumatoid arthritis, of which 34 are novel. A polygenic risk score based on multi-ancestry data showed comparable performance between populations of European and East Asian ancestries.Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 x 10(-8)), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.

Published
2022
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9. Sex-specific risk of anti-topoisomerase antibodies on mortality and disease severity in systemic sclerosis: 10-year analysis of the Leiden CCISS and EUSTAR cohorts

Author

Liem, Sophie I. E., Boonstra, Maaike, Le Cessie, Saskia, Riccardi, Antonella, Airo, Paolo, Distler, Oliver, Matucci-Cerinic, Marco, Caimmi, Cristian, Siegert, Elise, Allanore, Yannick, Tom Huizinga, Toes, Rene E. M., Scherer, Hans U., and Vries-Bouwstra, Jeska K.

Subjects
Rheumatology, Immunology, Immunology and Allergy
Published
2022
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10. [A man with polyarthralgia]

Author

Eliane A, Lucassen, W J Tom, Huizinga, and A J Jaap, Fogteloo

Subjects
Male, Erythema Nodosum, Sarcoidosis, Humans, Syndrome, Middle Aged, Arthralgia, Ghana
Abstract

A 46-year old Ghanaian man presented with immobilizing arthralgias in all joints except the forefoot, with a periarticular swelling most pronounced around the wrists and ankles. He had erythema nodosum and hilar lymphadenopathy on chest radiograph. We diagnosed Löfgren syndrome. The polyarthralgia recovered quickly with prednisone treatment.

Published
2022

11. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

Author

Mark Caulfield, Solbritt Rantapää Dahlqvist, Eleftheria Zeggini, Michael Weedon, Paul Martin, Elaine Dennison, Patricia Munroe, Detelina Grozeva, John Isaacs, Stephen Eyre, Alex MacGregor, Kate Duffus, Andrew Hattersley, DOROTHEE DIOGO, Luis Rodriguez-Rodriguez, Steven Young-Min, Chris Wallace, Miguel Gonzalez-Gay, Tom Huizinga, Stephen Newhouse, Alexandra Zhernakova, Melanie Newport, Deborah Symmons, Lisa Jones, Michael O'Donovan, Wan-Fai Ng, Nadira Yusupovna Yuldasheva, Cyrus Cooper, Willem Ouwehand, Philip Conaghan, Gerome Breen, Lars Alfredsson, Karim Raza, Hana Lango Allen, Jane Worthington, Mark Iles, Ann Morgan, Professor David Dunger, Soumya Raychaudhuri, Panos Deloukas, Marwan Bukhari, Alastair Forbes, Allan Young, Lars Klareskog, Leonid Padyukov, Fraser Birrell, Charlie Lees, Anne Barton, Martin Tobin, Patrick Concannon, Jon Packham, Natalie Prescott, Javier Martin, Kimme Hyrich, Lude Franke, John Bowes, Ian Bruce, Chiea Chuen Khor, Stephen Rich, Miles Parkes, Sarah Hunt, Tim Bishop, Gosia Trynka, Richard Dobson, Anna Dominiczak, Cisca Wijmenga, Mark McCarthy, Cecilia Lindgren, Rene Toes, Alistair Hall, Faculteit Medische Wetenschappen/UMCG, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Bowes, John [0000-0003-4659-031X], Zhernakova, Alexandra [0000-0002-4574-0841], Padyukov, Leonid [0000-0003-2950-5670], Toes, Rene EM [0000-0002-9618-6414], Wijmenga, Cisca [0000-0002-5635-1614], Trynka, Gosia [0000-0002-6955-9529], Franke, Lude [0000-0002-5159-8802], Alfredsson, Lars [0000-0003-1688-6697], Khor, Chiea Chuen [0000-0002-1128-4729], Concannon, Pat [0000-0002-5801-1859], Onengut-Gumuscu, Suna [0000-0002-6563-8334], Rodriguez-Rodriguez, Luis [0000-0002-2869-7861], Rantapää-Dahlqvist, Solbritt [0000-0001-8259-3863], Raychaudhuri, Soumya [0000-0002-1901-8265], Klareskog, Lars [0000-0001-9601-6186], and Apollo - University of Cambridge Repository

Subjects
EXPRESSION, Male, Arthritis, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, White People, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Gene mapping, Polymorphism (computer science), Genetics, medicine, SNP, Humans, CORONARY-HEART-DISEASE, Genetic Predisposition to Disease, Genotyping, METAANALYSIS, 030304 developmental biology, Genetic association, Autoantibodies, Oligonucleotide Array Sequence Analysis, 030203 arthritis & rheumatology, 0303 health sciences, Chromosome Mapping, ASSOCIATION, medicine.disease, RISK LOCI, INTERLEUKIN-6 RECEPTOR, Genetic Loci, Female, SNP array, Genome-Wide Association Study
Abstract

Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

Published
2021
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15. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

Author

Josef S Smolen, Robert Landewé, Johannes Bijlsma, Gerd Burmester, Katerina Chatzidionysiou, Maxime Dougados, Jackie Nam, Sofia Ramiro, Marieke Voshaar, Ronald van Vollenhoven, Daniel Aletaha, Martin Aringer, Maarten Boers, Chris D Buckley, Frank Buttgereit, Vivian Bykerk, Mario Cardiel, Bernard Combe, Maurizio Cutolo, Yvonne van Eijk-Hustings, Paul Emery, Axel Finckh, Cem Gabay, Juan Gomez-Reino, Laure Gossec, Jacques-Eric Gottenberg, Johanna M W Hazes, Tom Huizinga, Meghna Jani, Dmitry Karateev, Marios Kouloumas, Tore Kvien, Zhanguo Li, Xavier Mariette, Iain McInnes, Eduardo Mysler, Peter Nash, Karel Pavelka, Gyula Poór, Christophe Richez, Piet van Riel, Andrea Rubbert-Roth, Kenneth Saag, Jose da Silva, Tanja Stamm, Tsutomu Takeuchi, René Westhovens, Maarten de Wit, Désirée van der Heijde, Service de Rhumatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Département de Rhumatologie[Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Lapeyronie, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Rhumatologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut de biologie moléculaire et cellulaire ( IBMC ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Strasbourg, Immunologie des Maladies Virales et Autoimmunes ( IMVA - U1184 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Bicêtre, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Service de Rhumatologie [CHU Pellegrin], Groupe hospitalier Pellegrin, Immunology from Concept and Experiments to Translation ( ImmunoConcept ), Université de Bordeaux ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Service de rhumatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Service de rhumatologie [CHU Pitié Salpêtrière] (GRC-08 EEMOIS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Rheumatology, Smolen, Josef S, Landewé, Robert, Bijlsma, Johannes, Burmester, Gerd, Chatzidionysiou, Katerina, Dougados, Maxime, Nam, Jackie, Ramiro, Sofia, Voshaar, Marieke, van Vollenhoven, Ronald, Finckh, Axel, Gabay, Cem, AII - Inflammatory diseases, Epidemiology and Data Science, APH - Methodology, Ethics, Law & Medical humanities, Service de Rhumatologie [CHU Pitié Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Glucocorticoids/therapeutic use, Time Factors, Protein Kinase Inhibitors/therapeutic use, medicine.medical_treatment, Antirheumatic Agents/therapeutic use, DMARDs (biologic), PLACEBO-CONTROLLED TRIAL, law.invention, ACUTE-PHASE REACTANTS, Arthritis, Rheumatoid, 0302 clinical medicine, Randomized controlled trial, law, Immunology and Allergy, 030212 general & internal medicine, Janus Kinases/antagonists & inhibitors, Certolizumab pegol, INTERLEUKIN-6 RECEPTOR INHIBITION, skin and connective tissue diseases, ddc:616, Drug Substitution, DOSE GLUCOCORTICOID THERAPY, Antibodies, Monoclonal, ADALIMUMAB PLUS METHOTREXATE, RANDOMIZED CONTROLLED-TRIAL, 3. Good health, Antirheumatic Agents, TREAT-TO-TARGET, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Arthritis, Rheumatoid/drug therapy, Rheumatoid arthritis, Drug Therapy, Combination, DMARDs (synthetic), medicine.drug, musculoskeletal diseases, medicine.medical_specialty, Methotrexate/therapeutic use, Immunology, Antibodies, Monoclonal/therapeutic use, Rheumatoid Arthritis, General Biochemistry, Genetics and Molecular Biology, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], [ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 03 medical and health sciences, Rheumatology, RAPID RADIOGRAPHIC PROGRESSION, medicine, Humans, Disease-modifying antirheumatic drug, Intensive care medicine, Disease Activity, Glucocorticoids, Protein Kinase Inhibitors, Janus Kinases, STANDARDIZED OPERATING PROCEDURES, 030203 arthritis & rheumatology, business.industry, Tumor Necrosis Factor-alpha, Tumor Necrosis Factor-alpha/antagonists & inhibitors, Abatacept, Evidence-based medicine, medicine.disease, Treatment, Methotrexate, Patient Participation, business, Rheumatism, CARDIOVASCULAR RISK-MANAGEMENT
Abstract

International audience; Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to-or adding-another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies.

Published
2017
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16. Risk of rheumatoid arthritis development in patients with unclassified arthritis according to the 2010 ACR/EULAR criteria for rheumatoid arthritis

Author

Dirkjan van Schaardenburg, Abhishek Abhishek, A. Krabben, Tom Huizinga, K. Britsemmer, Annette H M van der Helm-van Mil, Andrew Filer, and Karim Raza

Subjects
Adult, Male, rheumatoid arthritis, musculoskeletal diseases, medicine.medical_specialty, Arthritis, Clinical prediction rule, Peptides, Cyclic, Arthritis, Rheumatoid, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Risk Factors, Surveys and Questionnaires, Internal medicine, medicine, Factor V Leiden, Humans, Pharmacology (medical), In patient, 030212 general & internal medicine, Medical prescription, skin and connective tissue diseases, Aged, prediction rule, 030203 arthritis & rheumatology, Predictive marker, business.industry, cyclic citrullinated peptide, Middle Aged, Prognosis, medicine.disease, Antibodies, Anti-Idiotypic, classification, arthritis, Antirheumatic Agents, Rheumatoid arthritis, Cohort, Disease Progression, outcome, Physical therapy, persistence disease, Female, unclassified arthritis, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Objective. Early recognition and treatment of RA is associated with an improved outcome. The 2010 ACR/ EULAR criteria for RA identify RA patients earlier than the 1987 ACR criteria. Nevertheless, we recently observed that 24% of the 2010 unclassified arthritis (UA) patients develop RA during follow-up. Here we studied this frequency in other cohorts and evaluated the prognostic accuracy of ACPA and the Leiden prediction rule in 2010 UA patients. Methods. The 2010 UA patients from three Early Arthritis Clinics were studied: 776 from Leiden, 121 from Birmingham and 322 from Amsterdam. Fulfilment of the 1987 ACR criteria during follow-up was studied as the primary outcome. DMARD prescription during the year and having a persistent course of arthritis over 7 years were studied as secondary outcomes in one cohort. The presence of ACPA and the prediction score at baseline were evaluated in relation to these outcomes. Results. In the three cohorts, 24%, 26% and 12%, respectively, of the 2010 UA patients fulfilled the 1987 criteria after 1 year. However, some of these patients already fulfilled the 1987 criteria at baseline. In 1987 and 2010 UA patients, 15%, 21% and 9%, respectively, developed RA (1987) at 1 year. In these patients, 06% of the patients were ACPA positive and 01% had high prediction scores. Consequently a large majority of the UA patients with an unfavourable outcome was not recognized by these prognostic tools. Conclusion. A proportion of 2010 UA patients progress to RA. ACPA and the Leiden prediction rule are not useful in identifying these patients. These results imply that other predictive markers should be developed for 2010 UA patients.

Published
2013
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23. Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry

Author

Francesco CUCCA, Neeraj Kumar, Luis Castaño, David Van Heel, James Lee, Andrew Hattersley, Valdis Pirags, Paolo Pozzilli, Farren Briggs, Maria Giovanna Marrosu, Paul Henderson, Neil Walker, Ondrej Cinek, Tom Huizinga, Francisco Javier Ampudia Blasco, Alexandra Zhernakova, Claire Vandiedonck, Mark A. Hall, Ana M Wägner, Charles Mein, Xiaoying Li, Matt Simmonds, Willem Ouwehand, Flemming Pociot, Didac Mauricio, Vaidotas Urbanavicius, Jennifer Couper, Adam Kretowski, Deborah Smyth, Graham Heap, Professor David Dunger, Federico Vázquez, Ian Nicholson, Ellen Schofield, Panos Deloukas, John Todd, Ingrid Kockum, Christopher George Mathew, Mikael Knip, Tadej Battelino, Thomas Brodnicki, Patrick Concannon, Jesús Argente, HU ZHANG, Kerstin Brismar, Peter Colman, Gurvinder Kaur, Natalie Prescott, Nicholas Bockett, Oliver Burren, Dr. S. Hofmann, Rohana Abdul Ghani, Stephan Weidinger, Marta Hernández, Jeffrey Barrett, William McLaren, Alessandro Doria, Stephen Rich, Magdalena Zoledziewska, Daniel Metzger, William Newman, Miles Parkes, Magdalena Avbelj Stefanija, Sarah Hunt, Jesper Johannesen, Zdenek Sumnik, Gosia Trynka, Steven Willi, Vallo Tillmann, Cisca Wijmenga, Oliver Brand, Rene Toes, University of Zurich, van Heel, David A, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Translational Immunology Groningen (TRIGR)

Subjects
Autoimmune disease, Genetics, 10265 Clinic for Endocrinology and Diabetology, Genetic Variation, CELIAC-DISEASE, 610 Medicine & health, Acetylesterase, Biology, medicine.disease, Article, White People, Autoimmune Diseases, 1311 Genetics, Gene Frequency, Risk Factors, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Allele frequency, Genetic Association Studies
Abstract

Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry

Published
2016

27. Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis

Author

René E. M. Toes, Diane van der Woude, Andreea Ioan-Facsinay, Ger J. M. Pruijn, Carla Onnekink, Carla M. Schwarte, Kirsten N Verpoort, Jan W. Drijfhout, Solbritt Rantapää-Dahlqvist, and Tom Huizinga

Subjects
musculoskeletal diseases, medicine.medical_specialty, Immunology, Arthritis, Peptides, Cyclic, General Biochemistry, Genetics and Molecular Biology, Epitope, Arthritis, Rheumatoid, Epitopes, Immune system, Rheumatology, Internal medicine, medicine, Humans, Immunology and Allergy, skin and connective tissue diseases, Autoantibodies, biology, business.industry, Bio-Molecular Chemistry, Anti–citrullinated protein antibody, Prognosis, medicine.disease, Connective tissue disease, rheumatoid-arthritis undifferentiated arthritis autoimmune arthritis shared epitope blood-donors autoantibodies peptides predict specificity progression, Rheumatoid arthritis, Disease Progression, biology.protein, Antibody, business, Follow-Up Studies
Abstract

Background Anti-citrullinated protein antibodies (ACPA) are the most predictive factor for the development of rheumatoid arthritis (RA). Objective To investigate whether the recognition of citrullinated epitopes changes during disease onset or progression, by studying the fine specificity of ACPA in serum samples collected throughout the disease course, from before the onset of arthritis to longstanding RA. Methods Antibodies recognising five distinct citrullinated antigens were determined by enzyme-linked immunosorbent assay. Serum samples from 36 individuals who had donated blood before and after disease manifestation were used to investigate the development of citrullinated antigen recognition before disease onset. The association of ACPA reactivities with disease outcome was studied using sera from anti-cyclic citrullinated peptide-2 (CCP2)-positive patients with undifferentiated arthritis (UA) who did or did not progress to RA (UA-RA n = 81, or UA-UA n = 35). To investigate the ACPA recognition profile in patients with RA over a prolonged period of time, baseline serum samples from 68 patients were compared with samples obtained 7 years later. Results The number of recognised citrullinated peptides increased in the period preceding disease onset. At the time of disease manifestation, patients with UA who later developed RA recognised significantly more peptides than UA-UA patients. At later stages of the disease course, the ACPA fine specificity did not change. Conclusion Epitope spreading with an increase in the recognition of citrullinated antigens occurs before the onset of RA. Immunological differences in ACPA fine specificity between UA-UA patients and UA-RA patients are present at baseline and are associated with the future disease course.

Published
2010
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30. In Rheumatoid Arthritis, Smoking Is Not Associated with Anti-Citrullinated Protein Antibodies per Se, but with the Concurrent Presence of Rheumatoid Factor, Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies

Author

Wesemael, Tineke, Muhammad, Ammar, Ajeganova, Sofia, Humphreys, Jennifer, Symmons, Deborah P. M., Macgregor, Alex J., Hafstrom, Ingiald, Trouw, Leendert, Tom Huizinga, Svensson, Bjorn, Toes, Ren E. M., Verstappen, Suzanne M., and Woude, Diane

Published
2015

33. On Drug and Drug-Free Remission by Baseline Disease Duration in the AVERT Trial: Abatacept versus Methotrexate Comparison in Patients with Early Rheumatoid Arthritis

Author

Bykerk, Vivian, Burmester, Gerd, Combe, Bernard, Furst, Daniel E., Tom Huizinga, Wong, Daniel, and Emery, Paul

Subjects
musculoskeletal diseases, ddc: 610, 610 Medical sciences, Medicine
Abstract

Introduction: Patients with RA and longer disease duration generally do not respond as well to treatment with DMARDs as patients with a shorter duration of disease. Earlier use of biologic DMARDs can improve disease control [ref:1], [ref:2]. The AVERT trial provides the opportunity[for full text, please go to the a.m. URL], 43. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 29. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 25. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Published
2015
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