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in category rheumatology

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1: Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study
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Posted 10 Apr 2020

Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study
34,230 downloads medRxiv rheumatology

Jennifer C. E. Lane, James Weaver, Kristin Kostka, Talita Duarte-Salles, Maria Tereza F. Abrahao, Heba Alghoul, Osaid Alser, Thamir M Alshammari, Patricia Biedermann, Edward Burn, Paula Casajust, Mitch Conover, Aedin C. Culhane, Alexander Davydov, Scott L DuVall, Dmitry Dymshyts, Sergio Fernández Bertolín, Kristina Fišter, Jill Hardin, Laura Hester, George Hripcsak, Seamus Kent, Sajan Khosla, Spyros Kolovos, Christophe G. Lambert, Johan ver der Lei, Kristine E Lynch, Rupa Makadia, Andrea V. Margulis, Michael E Matheny, Paras Mehta, Daniel R. Morales, Henry Morgan-Stewart, Mees Mosseveld, Danielle Newby, Fredrik Nyberg, Anna Ostropolets, Rae Woong Park, Albert Prats-Uribe, Gowtham A. Rao, Christian Reich, Jenna Reps, Peter Rijnbeek, Selva Muthu Kumaran Sathappan, Martijn Schuemie, Sarah Seager, Anthony G. Sena, Azza Shoaibi, Matthew Spotnitz, Marc A Suchard, Joel Swerdel, Carmen Olga Torre, David Vizcaya, Haini Wen, Marcel de Wilde, Seng Chan You, Lin Zhang, Oleg Zhuk, Patrick Ryan, DANIEL PRIETO-ALHAMBRA

BackgroundHydroxychloroquine has recently received Emergency Use Authorization by the FDA and is currently prescribed in combination with azithromycin for COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin. MethodsNew user cohort studies were conducted including 16 severe adverse events (SAEs). Rheumatoid arthritis patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine and followed up over 30 days. Self-controlled case series (SCCS) were conducted to further establish safety in wider populations. Separately, SAEs associated with hydroxychloroquine- azithromycin (compared to hydroxychloroquine-amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, UK, and USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (CalHRs) according to drug use. Estimates were pooled where I2<40%. ResultsOverall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin were included. No excess risk of SAEs was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. SCCS confirmed these findings. However, when azithromycin was added to hydroxychloroquine, we observed an increased risk of 30-day cardiovascular mortality (CalHR2.19 [1.22- 3.94]), chest pain/angina (CalHR 1.15 [95% CI 1.05-1.26]), and heart failure (CalHR 1.22 [95% CI 1.02- 1.45]) ConclusionsShort-term hydroxychloroquine treatment is safe, but addition of azithromycin may induce heart failure and cardiovascular mortality, potentially due to synergistic effects on QT length. We call for caution if such combination is to be used in the management of Covid-19. Trial registration numberRegistered with EU PAS; Reference number EUPAS34497 (http://www.encepp.eu/encepp/viewResource.htm?id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine. Funding sourcesThis research received partial support from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and Senior Research Fellowship (DPA), US National Institutes of Health, Janssen Research & Development, IQVIA, and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea [grant number: HI16C0992]. Personal funding included Versus Arthritis [21605] (JL), MRC-DTP [MR/K501256/1] (JL), MRC and FAME (APU). The European Health Data & Evidence Network has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 806968. The JU receives support from the European Unions Horizon 2020 research and innovation programme and EFPIA. No funders had a direct role in this study. The views and opinions expressed are those of the authors and do not necessarily reflect those of the Clinician Scientist Award programme, NIHR, NHS or the Department of Health, England.

2: Effect of Vitamin D3 Supplementation vs Placebo on Hospital Length of Stay in Patients with Severe COVID-19: A Multicenter, Double-blind, Randomized Controlled Trial.
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Posted 17 Nov 2020

Effect of Vitamin D3 Supplementation vs Placebo on Hospital Length of Stay in Patients with Severe COVID-19: A Multicenter, Double-blind, Randomized Controlled Trial.
6,011 downloads medRxiv rheumatology

Igor H. Murai, Alan L. Fernandes, Lucas P. Sales, Ana J. Pinto, Karla F. Goessler, Camila S. C. Duran, Carla B. R. Silva, André S. Franco, Marina B. Macedo, Henrique H. H. Dalmolin, Janaina Baggio, Guilherme G. M. Balbi, Bruna Z. Reis, Leila Antonangelo, Valeria F. Caparbo, Bruno Gualano, Rosa M. R. Pereira

ImportancePatients with COVID-19 may exhibit 25-hydroxyvitamin D deficiency, but the beneficial effects of vitamin D3 supplementation in this disease remain to be proven by randomized controlled trials. ObjectiveTo investigate the efficacy and safety of vitamin D3 supplementation in patients with severe COVID-19. Design, Setting, and ParticipantsThis is a multicenter, double-blind, randomized, placebo-controlled trial conducted in two centers (a quaternary hospital and a field hospital) in Sao Paulo, Brazil. The trial included 240 hospitalized patients with severe COVID-19. The study was conducted from June 2, 2020 to October 7, 2020. InterventionsPatients were randomly allocated (1:1 ratio) to receive either a single oral dose of 200,000 IU of vitamin D3 or placebo. Main Outcomes and MeasuresThe primary outcome was hospital length of stay, defined as hospital discharge from the date of randomization or death. Secondary outcomes were mortality, admission to ICU, mechanical ventilation requirement, and serum levels of 25-hydroxyvitamin D, creatinine, calcium, C-reactive protein, and D-dimer. ResultsOf 240 randomized patients (mean age, 56 years; 56% men), 232 (96.7%) were included in the primary analysis. Log-rank test showed that hospital length of stay was comparable between the vitamin D3 supplementation and placebo groups (7.0 days [95% CI, 6.1 to 7.9] and 7.0 days [95% CI, 6.2 to 7.8 days]; hazard ratio, 1.12 [95% CI, 0.9 to 1.5]; P = .379; respectively). The rate of mortality (7.0% vs 5.1%; P = .590), admission to ICU (15.8% vs 21.2%; P = .314), and mechanical ventilation requirement (7.0% vs 14.4%; P = .090) did not significantly differ between groups. Vitamin D3 supplementation significantly increased serum 25-hydroxyvitamin D levels compared to placebo (difference, 24.0 ng/mL [95% CI, 21.0% to 26.9%]; P = .001). No adverse events were observed. Conclusions and RelevanceAmong hospitalized patients with severe COVID-19, vitamin D3 supplementation was safe and increased 25-hydroxyvitamin D levels, but did not reduce hospital length of stay or any other relevant outcomes vs placebo. This trial does not support the use of vitamin D3 supplementation as an adjuvant treatment of patients with COVID-19. Key pointsO_ST_ABSQuestionC_ST_ABSCan vitamin D3 supplementation reduce hospital length of stay in hospitalized patients with severe COVID-19? FindingsIn this double-blind, randomized, placebo-controlled trial involving 240 hospitalized patients with severe COVID-19, a single dose of 200,000 IU of vitamin D3 supplementation was safe and effective in increasing 25-hydroxyvitamin D levels, but did not significantly reduce hospital length of stay (hazard ratio, 1.12) or any other clinically-relevant outcomes compared with placebo. MeaningVitamin D3 supplementation does not confer therapeutic benefits among hospitalized patients with severe COVID-19.

3: Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients
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Posted 04 Apr 2020

Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients
1,874 downloads medRxiv rheumatology

Amr H Sawalha, Ming Zhao, Patrick Coit, Qianjin Lu

Infection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specially, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NF{kappa}B, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.

4: Calming the Cytokine Storm - Splenic Ultrasound for Treating Inflammatory Disorders and Potentially COVID-19
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Posted 17 Jul 2020

Calming the Cytokine Storm - Splenic Ultrasound for Treating Inflammatory Disorders and Potentially COVID-19
1,235 downloads medRxiv rheumatology

Rachel Stegeman Graham, Daniel P Zachs, Victoria Cotero, Catherine DAgostino, Despoina Ntiloudi, Claire RW Kaiser, John Graf, Kirk Wallace, Thomas R Coleman, Jeffrey Ashe, John Pellerito, Kevin J. Tracey, Bryce Binstadt, Sangeeta S. Chavan, Stavros Zanos, Christopher Puleo, Erik Peterson, Hubert H. Lim

Hyperinflammation and uncontrolled cytokine release in infections and autoimmune diseases require therapy to reduce the innate immune response. Here, we present first in-human data showing reduction in pro-inflammatory cytokine release with ultrasound stimulation of the spleen in healthy subjects and in rheumatoid arthritis patients. Single cell RNA sequencing reveals a decrease in IL-1{beta} and IL-8 transcript levels in circulating monocytes. There is also a down regulation of pathways involved in TNF and IL-6 production, and genes regulated by IFN and NF{kappa}B. Additional pre-clinical studies reveal that ultrasound can boost B cell activation and antibody production. Splenic ultrasound offers a new non-invasive therapy for treating hyperinflammation without compromising the adaptive immune response

5: Incidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases treated with targeted biologic and synthetic disease-modifying anti-rheumatic drugs
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Posted 05 May 2020

Incidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases treated with targeted biologic and synthetic disease-modifying anti-rheumatic drugs
1,063 downloads medRxiv rheumatology

Xabier Michelena, Helena Borrell, Mireia Lopez-Corbeto, Maria Lopez-Lasanta, Estefania Moreno, Maria Pascual-Pastor, Alba Erra, Mayte Serrat, Esther Espartal, Susana Anton, Gustavo A Anez, Raquel Caparros-Ruiz, Andrea Pluma, Ernesto Trallero-Araguas, Mireia Barcelo-Bru, Miriam Almirall, Juan Jose De Agustin, Jordi Llados, Antonio Julia, Sara Marsal

OBJECTIVES: To investigate the incidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases receiving targeted biologic and synthetic disease modifying anti-rheumatic drugs (tDMARDs) and to explore the possible effect of these treatments in the clinical expression of COVID-19. METHODS: A cross-sectional study comprising of a telephone survey and electronic health records review was performed including all adult and paediatric patients with rheumatic diseases treated with tDMARDs in a large rheumatology tertiary centre in Barcelona, Spain. Demographics, disease activity, COVID-19 related symptoms and contact history data were obtained from the start of the 2020 pandemic. Cumulative incidence of confirmed cases (SARS-CoV-2 positive PCR test) was compared to the population estimates for the same city districts from a governmental COVID-19 health database. Suspected cases were defined following WHO criteria and compared to those without compatible symptoms. RESULTS: 959 patients with rheumatic diseases treated with tDMARDs were included. We identified 11 confirmed SARS-CoV-2 positive cases in the adult cohort and no confirmed positive cases in the paediatric cohort. All patients had a successful recovery and only one patient required admission in the intensive care unit. When using the same classification criteria (only COVID-19 positive cases with pneumonia), COVID-19 incidence rates of the rheumatic patient cohort were very similar to that of the general population [(0.48% (95% CI 0.09 to 8.65%)] and [0.58% (95% CI 5.62 to 5.99%)], respectively. We found significant differences in tDMARDs proportions between the suspected and non-suspected cases (p=0.002). CONCLUSION: Adult and paediatric patients with rheumatic diseases on tDMARDs do not seem to present a higher risk of COVID-19 or a more severe disease outcome when compared to general population. Our exploratory analysis suggests that the proportion of COVID-19 suspected cases differs between tDMARDs.

6: Management of rheumatic diseases in the times of COVID-19 pandemic- perspectives of rheumatology practitioners from India
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Posted 07 Apr 2020

Management of rheumatic diseases in the times of COVID-19 pandemic- perspectives of rheumatology practitioners from India
1,041 downloads medRxiv rheumatology

Latika Gupta, Durga Prasanna Misra, Vishwesh Agarwal, Suma Balan, Vikas Agarwal

ObjectiveThe Coronavirus disease 19 (COVID-19) pandemic has led to widespread concerns about the risk of infection in patients with rheumatic diseases (RD) receiving disease modifying ant-rheumatic drugs (DMARDs) and other immunosuppressants (IS). MethodsA SurveyMonkey(R) based electronic survey was conducted amongst members of the Indian Rheumatology Association to understand the need for changes in prevailing practices. ResultsOf the 861 invitees, 221 responded. In the wake of the pandemic, 47.5% would reduce biological DMARDs (bDMARDs) while only 12.2% would reduce the use of conventional synthetic DMARDs. 64.2% were likely to defer change in IS, the reluctance being most with rituximab (58.3%) followed by cyclophosphamide (53.3%), anti-tumor necrosis factor alpha agents (52.4%) and Janus kinase inhibitors (34.39%). Hydroxychloroquine was the preferred choice (81.9%) for the treatment of COVID-19 followed by protease inhibitors (22.1%) and intravenous immunoglobulin (8.1%). Chloroquine was less preferred (19%). More than two-thirds (70.5%) believed that COVID-19 might trigger macrophage activation syndrome. Social distancing (98.1%) and hand hygiene (74.6%) were recommended by majority. 62.8% would avoid touch for clinical examination whenever feasible. ConclusionMost rheumatologists perceived the need to change treatment of RDs during the COVID-19 pandemic; reduce immunosuppression and defer the usage of rituximab and bDMARDs. Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABSPatients with rheumatic diseases receiving glucocorticoids, disease modifying ant-rheumatic drugs and other immunosuppressants have increased susceptibility to infections including respiratory tract infections What does this study add?{circ} There is an urgent need to revise the management of rheumatic diseases as perceived by a large group of practicing rheumatologists in India in the times of the COVID-19 pandemic. {circ}There is reluctance to initiate biological DMARDs (especially Rituximab and anti-TNF agents), tsDMARDs (JAK inhibitors) and cyclophosphamide. {circ}There is an inclination to prescribe hydroxychloroquine (HCQ) even for rheumatic diseases with weak level of evidence. How might this impact on clinical practice?This might identify areas to be addressed in a Delphi exercise to develop expert evidence to guide the management of RDs during the pandemic.

7: Hospital admissions in inflammatory rheumatic diseases during the COVID-19 pandemic: incidence and role of disease modifying agents
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Posted 23 May 2020

Hospital admissions in inflammatory rheumatic diseases during the COVID-19 pandemic: incidence and role of disease modifying agents
861 downloads medRxiv rheumatology

Benjamin Fernandez-Gutierrez, Leticia Leon, Alfredo Madrid, Luis Rodriguez-Rodriguez, Dalifer Freites, Judit Font, Arkaitz Mucientes, Jose Ignacio Colomer, Juan Angel Jover, Lydia Abasolo

Background: In this pandemia, it is essential for rheumatologist and patients to know the relationship between COVID-19 and inflammatory rheumatic diseases (IRD). We want to assess the role of targeted synthetic or biologic disease modifying antirheumatic drugs (ts/bDMARDs) and other variables in the development of moderate-severe COVID-19 disease in IRD. Methods: An observational longitudinal study was conducted (1stMar to 15thApr 2020). All patients from the rheumatology outpatient clinic from a hospital in Madrid with a medical diagnosis of IRD were included. Main outcome: hospital admission related to COVID-19. Independent variable: ts/bDMARDs. Covariates: sociodemographic, comorbidities, type of IRD diagnosis, glucocorticoids, NSAIDs and conventional synthetic DMARDs (csDMARDs). Incidence rate (IR) of hospital admission related to COVID-19, was expressed per 1,000 patients-month. Cox multivariate regression analysis was run to examine the influence of ts/bDMARDs and other covariates on IR. Results: 3,591 IRD patients were included (5,896 patients-month). Concerning csDMARDs, methotrexate was the most used followed by antimalarials. 802 patients were on ts/bDMARDs, mainly anti-TNF agents, and rituximab. Hospital admissions related to COVID-19 occurred in 54 patients (1.36%) with an IR of 9.15 [95%CI: 7-11.9]. In the multivariate analysis, older, male gender, presence of comorbidities and specific systemic autoimmune conditions (Sjoegren, polychondritis, Raynaud and mixed connective tissue disease) had more risk of hospital admissions regardless other factors. Exposition to ts/bDMARDs did not achieve statistical signification. Use of glucocorticoids, NSAIDs, and csDMARDs dropped from the final model. Conclusion: This study provides additional evidence in IRD patients regarding susceptibility to moderate-severe infection related to COVID-19.

8: An emergent, high-fatality lung disease in systemic juvenile arthritis
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Posted 20 Aug 2019

An emergent, high-fatality lung disease in systemic juvenile arthritis
798 downloads medRxiv rheumatology

Vivian E. Saper, Guangbo Chen, Gail Deutsch, R Paul. Guillerman, Johannes Birgmeier, Karthik Jagadeesh, Scott Canna, Grant Schulert, Robin Deterding, Jianpeng Xu, Ann N. Leung, Layla Bouzoubaa, Khalid Abulaban, Kevin Baszis, Edward M. Behrens, James Birmingham, Alicia Casey, Michal Cidon, Randy Cron, Aliva De, Fabrizio De Benedetti, Ian Ferguson, Martha P. Fishman, Steven I. Goodman, Brent Graham, Alexei Grom, Kathleen Haines, Melissa Hazen, Lauren A. Henderson, Assunta Ho, Maria Ibarra, CJ Inman, Rita Jerath, Khulood Walid Khawaja, Daniel J Kingsbury, Marisa Klein-Gitelman, Khan Lai, Sivia Lapidus, Clara Lin, Jenny Lin, Deborah R. Liptzin, Diana Milojevic, Joy Mombourquette, Karen Onel, Seza Ozen, Maria Perez, Kathryn Phillippi, Sampath Prahalad, Suhas Radhakrishna, Adam Reinhardt, Mona Riskalla, Natalie Rosenwasser, Johannes Roth, Rayfel Schneider, Dieneke Schonenberg-Meinema, Susan Shenoi, Judith A. Smith, Hafize Emine Sonmez, Matthew L. Stoll, Christopher Towe, Sara O. Vargas, Richard K Vehe, Lisa R. Young, Jacqueline Yang, Tushar Desai, Raymond Balise, Ying Lu, Lu Tian, Gil Bejerano, Mark M. Davis, Purvesh Khatri, Elizabeth D Mellins, the Childhood Arthritis and Rheumatology Research Alliance Registry Investigators

ObjectiveTo investigate characteristics and risk factors of a novel parenchymal lung disease, increasingly detected in systemic juvenile idiopathic arthritis (sJIA). MethodsIn a multi-center retrospective study, 61 cases were investigated, using physician-reported clinical information and centralized analyses of radiologic, pathologic and genetic data. ResultsLung disease (LD) was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the IL-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes +/- ground glass opacities. Predominant pathology (23/36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features, including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. 5-year survival was 42%. Whole-exome sequencing (20/61) did not identify a novel monogenic defect PAP-related or macrophage activation syndrome (MAS)-related mutations as likely primary cause. Trisomy 21 (T21) increased LD risk, as did young sJIA onset. Refractory sJIA was not required for LD development. Exposure to interleukin (IL)-1 and IL-6 inhibitors (46/61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but it was not associated with LD features. ConclusionsA rare, life-threatening LD in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

9: Prevalence of Hospital PCR Confirmed Covid-19 Cases in Patients with Chronic Inflammatory and Autoimmune Rheumatic Diseases
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Posted 14 May 2020

Prevalence of Hospital PCR Confirmed Covid-19 Cases in Patients with Chronic Inflammatory and Autoimmune Rheumatic Diseases
797 downloads medRxiv rheumatology

José L Pablos, Lydia Abasolo-Alcázar, José M. Álvaro-Gracia, Francisco J. Blanco, Ricardo Blanco, Isabel Castrejón, David Fernández-Fernández, Benjamín Fernández-Gutierrez, María Galindo, Miguel A. González-Gay, Sara Manrique-Arija, Natalia Mena-Vázquez, Antonio Mera-Varela, Miriam Retuerto, Álvaro Seijas-Lopez, RIER investigators group

ABSTRACT Background. The susceptibility of patients with rheumatic diseases, and the risks or benefits of immunosuppressive therapies for COVID-19 are unknown. Methods. We performed a retrospective study with patients under follow-up in rheumatology departments from seven hospitals in Spain. We matched updated databases of rheumatology patients with SARS-CoV-2 positive PCR tests performed in the hospital to the same reference populations. Rates of PCR+ confirmed COVID-19 were compared among groups. Results. Patients with chronic inflammatory diseases had 1.32-fold higher prevalence of hospital PCR+ COVID-19 than the reference population (0.76% vs 0.58%). Systemic autoimmune or immune mediated diseases (AI/IMID) patients showed a significant increase, whereas inflammatory arthritis (IA) or systemic lupus erythematosus (SLE) patients did not. COVID-19 cases in some but not all diagnostic groups had older ages than cases in the reference population. IA patients on targeted-synthetic or biological disease-modifying antirheumatic drugs (ts/bDMARD), but not those on conventional-synthetic (csDMARD), had a greater prevalence despite a similar age distribution. Conclusion. Patients with AI/IMID show a variable risk of hospital diagnosed COVID-19. Interplay of aging, therapies, and disease specific factors seem to contribute. These data provide a basis to improve preventive recommendations to rheumatic patients and to analyze the specific factors involved in COVID-19 susceptibility.

10: A COVID-19 outbreak in a rheumatology department upon the early days of the pandemic
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Posted 08 Jun 2020

A COVID-19 outbreak in a rheumatology department upon the early days of the pandemic
783 downloads medRxiv rheumatology

Vasco C. Romão, Filipa Oliveira-Ramos, Ana Rita Cruz-Machado, Patrícia Martins, Sofia Barreira, Joana Silva-Dinis, Luís Galaio, Helena Proença, José Melo Cristino, Ema Sacadura-Leite, Nikita Khmelinskii, José Carlos Romeu, João Eurico Fonseca, CHULN Rheumatology Department

Objectives: To describe our experience with a coronavirus disease 2019 (COVID-19) outbreak within a large rheumatology department, early in the pandemic. Methods: Symptomatic and asymptomatic healthcare workers (HCWs) had a naso-oropharyngeal swab for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and were followed clinically. Reverse transcription polymerase-chain reaction (RT-PCR) was repeated to document cure, and serological response was assessed. Patients with risk contacts within the department in the 14 days preceding the outbreak were screened for COVID-19 symptoms. Results: 14/34 HCWs (41%; 40{+/-}14 years, 71% female) tested positive for SARS-CoV-2, and 11/34 (32%) developed symptoms but were RT-PCR-negative. Half of RT-PCR-positive HCWs did not report fever, cough, or dyspnoea before testing, which were absent in 3/14 cases (21%). Mild disease prevailed (79%), but 3 HCWs had moderate disease requiring further assessment, which excluded severe complications. Nevertheless, symptom duration (28{+/-}18 days), viral shedding (31{+/-}10 days post-symptom onset, range 15-51) and work absence (29{+/-}28 days) were prolonged. 13/14 (93%) of RT-PCR-positive and none of the RT-PCR-negative HCWs had a positive humoral response, with higher IgG-index in individuals over 50 years (14.5{+/-}7.7 vs 5.0{+/-}4.4, p=0.012). Of 617 rheumatic patients, 8 (1.3%) developed COVID-19 symptoms (1/8 hospitalisation, 8/8 complete recovery), following a consultation/procedure with an asymptomatic (7/8) or mildly-symptomatic (1/8) HCW. Conclusions: A COVID-19 outbreak can occur among HCWs and rheumatic patients, swiftly spreading over the presymptomatic stage. Mild disease without typical symptoms should be recognised, and may evolve with delayed viral shedding, prolonged recovery, and adequate immune response in most individuals.

11: Use of Physician Global Assessment (PGA) in Systemic lupus erythematosus: a systematic review of its psychometric properties
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Posted 17 Apr 2020

Use of Physician Global Assessment (PGA) in Systemic lupus erythematosus: a systematic review of its psychometric properties
777 downloads medRxiv rheumatology

Elisabetta CHESSA, Matteo PIGA, Alberto Floris, Herve DEVILLIERS, Alberto Cauli, Laurent ARNAUD

Background: Physician Global Assessment (PGA) is a visual analogue score (VAS) that reflects the clinician's judgment of overall Systemic Lupus Erythematosus (SLE) disease activity. The aim of this systematic literature review (SLR) is to describe and analyse the psychometric properties of PGA. Methods: This SLR was conducted by two independent reviewers in accordance with the PRISMA statement. All articles published until the 1st of July 2019 in Pubmed were screened with no limitation about years of publication, language or patients' age. Psychometric properties data were analysed according to the OMERACT Filter methodology version 2.1. Results: The literature search identified 91 studies. Face validity was reported in all the articles retrieved, in which the PGA was used alone or as part of composite indices (SRI, SFI, LLDAS, DORIS remission criteria). Content validity was reported in 89 studies. Construct validity was demonstrated by a good correlation between the PGA with the SLEDAI (12 studies), SLAM (4 studies), LAI, BILAG and ECLAM (2 studies each). Criterion validity was assessed exploring the PGA correlation with quality of life measurements, biomarkers levels and treatment changes in 28 studies, while no study has evaluated correlation with damage. A good responsiveness for PGA was shown in 8 studies. A high variability in scales was found, causing a wide range of reliability (ICC=0.67-0.98). Conclusion: PGA is a valid, responsive and feasible instrument, while its reliability was impacted by the scale adopted, suggesting the major need for a standardization of its scoring.

12: COVID-19 AND PATIENTS UNDERGOING PHARMACOLOGICAL TREATMENTS FOR IMMUNE-MEDIATED INFLAMMATORY DISEASES: PROTOCOL FOR A RAPID LIVING SYSTEMATIC REVIEW
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Posted 06 May 2020

COVID-19 AND PATIENTS UNDERGOING PHARMACOLOGICAL TREATMENTS FOR IMMUNE-MEDIATED INFLAMMATORY DISEASES: PROTOCOL FOR A RAPID LIVING SYSTEMATIC REVIEW
752 downloads medRxiv rheumatology

Aline Pereira Rocha, Alvaro Nagib Atallah, Ana Carolina Pereira Nunes Pinto, Cesar Ramos Rocha-Filho, Felipe Sebastiao de Assis Reis, Keilla Machado Martins Milby, Vinicius Tassoni Civile, Nelson Carvas Junior, Rodolfo Rodrigo Pereira Santos, Laura Jantsch Ferla, Giulia Fernandes Moca Trevisani, Gabriel Sodre Ramalho, Maria Eduarda Santos Puga, Virginia Fernandes Moca Trevisani

CONTEXT AND OBJECTIVE: We propose to systematically review the available evidence to evaluate if patients with immune mediated inflammatory diseases under pharmacological treatment with immunosuppressants, immunobiologics, Disease-Modifying Anti-Rheumatic Drugs (DMARD) or targeted synthetic DMARDs have better or worse outcomes when infected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This study is a protocol for our rapid living systematic review. METHODS: Protocol for a rapid living systematic review methodology following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidance. To conduct the rapid systematic review, we will employ abbreviated systematic review methods, including: not performing independent screens of abstracts and not searching grey literature. As this will be a living review, it will be continuously updated.

13: HYDROXICLOROQUINE FOR PRE-EXPOSURE PROPHYLAXIS FOR SARS-CoV-2
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Posted 02 Sep 2020

HYDROXICLOROQUINE FOR PRE-EXPOSURE PROPHYLAXIS FOR SARS-CoV-2
737 downloads medRxiv rheumatology

Jaime Lopez de la Iglesia, Naiara Cubelos, Roi Naveiro, Marina Montoro Gomez, Francisco Javier Gonzalez de Haro, Maria Ajenjo Gonzalez, Estefania Tobal Vicente, Maria Lamuedra Gil de Gomez, Maria Teresa Nuevo Guisado, Isabel Torio Gomez, Ana Penalver Andrada, Nuria Martinez Cao, Paula Gonzalez Figaredo, Carlos Robles Garcia, Lidia Anastasia Alvarado Machon, Angeles Lafont Alcalde, Jose Cesareo Naveiro Rilo

SARS-CoV-2 infection has a high transmission level. At the present time there is not a specific treatment approved but it is known that, in vitro, chloroquine and hydroxychloroquine can inhibit the coronavirus. Objective: verifying if patients with autoimmune diseases that are on treatment with HCQ have less incidence and severity on COVID-19. Material and methods: this is a retrospective cohort study. The exposed cohort was formed by individuals with autoimmune diseases with HCQ treatment. The control cohort was randomly selected using the Health Card database. To deal with confounding variables and evaluate the effect of HCQ on the incidence and severity of SARS-CoV-2 infection, propensity score matching was used. Risk difference and paired percentage difference between exposed and non-exposed groups was estimated. Results: 919 individuals formed the exposed cohort and 1351 the control cohort. After matching, there were 690 patients on each group. During the time of the study, in the exposed group there were 42 (6.1%) individuals with suspected COVID-19, 12(1.7%) with confirmed COVID-19 and 3(0.4%) were hospitalized. In the control group there were 30(4.3%) individuals with suspected COVID-19, 13(1.9%) with confirmed COVID-19 and 2(0.3%) were hospitalized. The risk difference between each cohort was: 0.017(-0.05-0.04) for suspected COVID-19; -0.014(-0.015-0.012) for confirmed COVID-19 and 0.001(-0.007-0.007) for hospitalized patients. There were not significant differences. Conclusion: there is no difference neither on the incidence nor on the severity of COVID-19 between patients with autoimmune diseases with HCQ treatment and patients that do not take HCQ.

14: Clinical Outcomes of Patients with COVID-19 and Chronic Inflammatory and Autoimmune Rheumatic Diseases: A Multicentric Matched-Cohort Study
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Posted 20 Jun 2020

Clinical Outcomes of Patients with COVID-19 and Chronic Inflammatory and Autoimmune Rheumatic Diseases: A Multicentric Matched-Cohort Study
716 downloads medRxiv rheumatology

José L Pablos, María Galindo, Loreto Carmona, Miriam Retuerto, Ana Lledó, Ricardo Blanco, Miguel A. González-Gay, David Martínez-López, Isabel Castrejón, José M. Alvaro-Gracia, David Fernández-Fernández, Antonio Mera-Varela, Sara Manrique-Arija, Natalia Mena-Vázquez, Antonio Fernández-Nebro, RIER investigators group

ABSTRACT Background The impact of inflammatory rheumatic diseases on COVID-19 severity is poorly known. Here we compare the outcomes of a cohort of rheumatic patients with a matched control cohort to identify potential risk factors for severe illness. Methods In this comparative cohort study, we identified hospital PCR+ COVID-19 rheumatic patients with chronic inflammatory arthritis (IA) or autoimmune/immunomediated diseases (AI/IMID). Non-rheumatic controls were randomly sampled 1:1, and matched by age, sex, and PCR date. The main outcome was severe COVID-19, defined as death, invasive ventilation, ICU admission, or serious complications. We assessed the association between the outcome and potential prognostic variables, adjusted by COVID treatment, using logistic regression. Results The cohorts were composed of 456 rheumatic and non-rheumatic patients, in equal numbers. Mean age was 63 [IQR 53-78] and male sex 41% in both cohorts. Rheumatic diseases were IA (60%) and AI/IMID (40%). Most patients (74%) had been hospitalised, and the risk of severe COVID was 31.6% in the rheumatic and 28.1% in the non-rheumatic cohort. Ageing, male sex and previous comorbidity (obesity, diabetes, hypertension, cardiovascular, or lung disease) increased the risk in the rheumatic cohort by bivariate analysis. In logistic regression analysis, independent factors associated with severe COVID were increased age (OR 5.31; CI 3.14-8.95), male sex (2.13; CI 1.35-3.36) and having an AI/IMID (OR 1.98; CI 1.15-3.41). Conclusion In patients with chronic inflammatory rheumatic diseases aging, sex and having an AI/IMID but not IA nor previous immunosuppressive therapies were associated with severe COVID-19.

15: BEYOND BONES - THE RELEVANCE OF VARIANTS OF CONNECTIVE TISSUE (HYPERMOBILITY) TO FIBROMYALGIA, ME/CFS AND CONTROVERSIES SURROUNDING DIAGNOSTIC CLASSIFICATION: AN OBSERVATIONAL STUDY
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Posted 23 Feb 2020

BEYOND BONES - THE RELEVANCE OF VARIANTS OF CONNECTIVE TISSUE (HYPERMOBILITY) TO FIBROMYALGIA, ME/CFS AND CONTROVERSIES SURROUNDING DIAGNOSTIC CLASSIFICATION: AN OBSERVATIONAL STUDY
705 downloads medRxiv rheumatology

Jessica A Eccles, Beth Thompson, Kristy Themelis, Marisa Amato, Robyn Stocks, Amy Pound, Anna-Marie Jones, Zdenka Cipinova, Lorraine Shah-Goodwin, Jean Timeyin, Charlotte R Thompson, Thomas Batty, Neil A Harrison, Hugo Critchley, Kevin A Davies

ObjectivesTo understand the relevance of symptomatic hypermobility and related connective tissue variants to the expression of symptoms in Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The study further tested if specific subfactors within the diagnostic classification of hypermobility predict clinical presentations. DesignWe report part of a larger case-control study exploring mechanisms of chronic pain and fatigue in Fibromyalgia and ME/CFS (https://doi.org/10.1186/ISRCTN78820481) Settingan NHS Clinical Research Facility. ParticipantsA subsample of 87 participants were assessed for symptomatic hypermobility by a trained clinician: 63 presented with a clinical diagnosis of either Fibromyalgia and or ME/CFS confirmed at screening; 24 participants were confirmed as healthy controls. Main outcome measures1) Brighton Criteria for joint hypermobility syndrome and 2017 hEDS diagnostic criteria. 2) ACR 2010 Diagnostic Criteria for Fibromylagia and Canadian and Fukada diagnostic criteria for ME/CFS. 3) Self report measures of subjective pain, fatigue and interoceptive sensibility. ResultsTwenty of the 63 patients (32%) presented with a clinical diagnosis of Fibromyalgia; 24 (38%) with a clinical diagnosis of ME/CFS and 19 (30%) with dual diagnoses of fibromyalgia and ME/CFS. After evaluation using clinical research tools, 56 patients (89%) met ACR diagnostic criteria for fibromyalgia; 59 (94%) Canadian Criteria for ME/CFS; and 61 (97%) Fukada Criteria for ME/CFS. After research evaluation 52 patients (85%) in fact met diagnostic criteria for Fibromyalgia and ME/CFS on all three sets of tools (ACR, Canadian, Fukada). In addition, 51 patients (81%) and 9 (37.5%) healthy controls met Brighton Criteria for joint hypermobility syndrome and 11 (18%) and 2 (8%) of patients and controls respectively, on the 2017 hEDS criteria. Of these patient participants with symptomatic hypermobility only 12 (23.5%) had received a prior diagnosis of hypermobility. Across all participants meeting Brighton Criteria, 13 (22%) also endorsed a hEDS diagnosis. Membership of the patient group was predicted by meeting the Brighton Criteria for joint hypermobility syndrome (p=<0.001, OR 7.08, 95%CI 2.50 - 20.00), but not by meeting the hEDS criteria. The historical, rather than current Beighton score correlated with; 1) total pain reported on the McGill Pain Questionnaire (short form), (r= 0.25, n= 73, p=0.03); 2) Widespread Pain Index (derived from ACR diagnostic criteria) (r=0.26, n= 86, p=0.01); 3) ACR symptom severity (r=0.27, n=85, p=0.01); 4) Fatigue Impact (r=0.29, n=56, p=0.28); and 5) interoceptive sensibility (r=0.30, n=56, p=0.02). ConclusionsSymptomatic joint hypermobility is relevant to symptoms and diagnosis in Fibromyalgia and ME/CFS. These conditions are poorly understood yet have a considerable impact on quality of life. Further work is needed to determine the prevalence of hEDS within the general population and define the critical clinical dimensions within symptomatic hypermobility. It is important to note the high rates of mis/underdiagnosis of symptomatic hypermobility in this group. Moreover, we need to clarify the role of variant connective tissue in dysautonomic and inflammatory mechanisms implicated in the expression of pain and fatigue in fibromyalgia and ME/CFS. Our observations have implications for diagnosis and treatment targets. Study registrationISCRTN78820481

16: Does Biological Therapy Protect against Severe COVID-19?
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Posted 24 Jun 2020

Does Biological Therapy Protect against Severe COVID-19?
689 downloads medRxiv rheumatology

Ramon Mazzucchelli, Raquel Almodovar-Gonzalez, Natalia Crespi-Villarias, Elena Garcia-Zamora, Elia Perez-Fernandez, Javier Quiros-Donate, Monserrat Perez-Encinas, Patricia Sanmartin-Fenollera, Maria Velasco-Arribas, Pilar Lopez-Serrano, Jose lazaro Perez-Calle, Conrado Fernandez-Rodriguez, Jose Luis Lopez-Estebaranz, Pedro Zarco-Montejo

Objective. To estimate COVID-19 infection incidence rate with severe affectation (requiring hospitalization) in patients with biological treatment due to rheumatoid arthritis (RA), psoriatic arthritis (PsA), spondyloarthritis (SpA), psoriasis (Ps), and inflammatory bowel disease (IBD) and compare it with incidence rate in the general population. Methods: Retrospective observational study based on information provided by two administrative databases. One of these two databases contains information on all patients seen in our hospital and diagnosed with COVID-19 infection between March 4th 2020 and April 26th 2020. The other database contains data from patients seen at Rheumatology, Dermatology and Digestive Departments in our hospital who are currently receiving biological therapy. We calculated the crude and age and sex adjusted incidence in both groups. To compare both groups we calculated the Incidence Rate Ratio. Results: There was a total of 2,182 patients with COVID-19 requiring hospitalization. Four patients out of a total of 797 patients receiving biological therapy had contracted COVID-19 and required hospital care. Crude incidence rate of COVID-19 requiring hospital care among the general population was 1.41%, and it was 0.50% among the group receiving biological therapy. Rates adjusted by age and sex in the biological group was 0.45% (CI95% 0.11-4.13). The IRR of the group receiving biological therapy compared to the general population was 0.39 (CI95% 0.14-1, p=0.049). Conclusion: Findings suggest that prior use of biological therapy does not associate with severe manifestations of COVID-19, and it is likely to have a protective effect against them when compared to the general population.

17: Risk of death among people with rare autoimmune diseases compared to the general population in England during the 2020 COVID-19 pandemic.
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Posted 11 Oct 2020

Risk of death among people with rare autoimmune diseases compared to the general population in England during the 2020 COVID-19 pandemic.
643 downloads medRxiv rheumatology

Emily Peach, Megan Rutter, Peter Lanyon, Matthew J Grainge, Richard Hubbard, Jeanette Aston, Mary Bythell, Sarah Stevens, Fiona Pearce

ObjectivesTo quantify the risk of death among people with rare autoimmune rheumatic diseases (RAIRD) during the UK 2020 COVID-19 epidemic compared with baseline risk and the risk of death in the general population during COVID-19. DesignA cohort study using data from the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS). We used ONS published data for general population mortality rates. SettingHospital Episode Statistics for England 2003 onwards, and linked data from the NHS Personal Demographics Service. Participants168,691 people with RAIRD who were alive on 1 March 2020. Their median age was 61.7 (IQR 41.5-75.4) years, and 118,379 (70.2%) were female. Our case ascertainment methods had a positive predictive value >85%. Main outcome measureAge-standardised mortality rates for all-cause death. Secondary outcome measures were age-sex standardised mortality rates, and age-stratified mortality rates. Results1,815 (1.1%) participants died during March and April 2020. The age-standardised mortality rate (ASMR) among people with RAIRD (3669.3, 95% CI 3500.4-3838.1 per 100,000 person-years) was 1.44 (95% CI 1.42-1.45) times higher than the average ASMR during the same months of the previous 5 years, whereas in the general population of England it was 1.38 times higher. Compared to the general population, the age-specific mortality rates in people with RAIRD compared to the pre-COVID rates were higher from the age of 35 upwards, whereas in the general population the increased risk began from age 55 upwards. Sex-specific rates were similar in males and females, whereas in the general population females had a lower rate than males. ConclusionsThe risk of all-cause death is more prominently raised during COVID-19 among people with RAIRD than among the general population. We urgently need to quantify how much risk is due to COVID-19 infection and how much is due to disruption to healthcare services, in order to inform better guidance about shielding, access to healthcare and vaccine priorities for people with rare diseases. Key messagesO_ST_ABSWhat is already known on this topic?C_ST_ABSPeople with rare diseases often suffer worse health outcomes than people with more common diseases. Little is known about the risks to people with rare diseases during COVID-19. The OPENSAFELY study found people with common autoimmune diseases were at little increased risk due to COVID-19. What this study addsThis is the first study to quantify the risk of death among people with rare autoimmune rheumatic diseases (RAIRD) during COVID-19. People with rare autoimmune rheumatic diseases (RAIRD) had an increased risk of death compared to their pre-COVID risk that is slightly higher than in the general population. People with RAIRD had an increased risk of death, compared to their pre-COVID risk, from age 35 upwards, whereas in the general population the increased risk occurred from around age 55 upwards. Because females and males with RAIRD had similar age-standardised mortality rates during COVID-19, but females had lower rates pre-COVID and in the general population during COVID-19, the group at the largest increase of risk compared to their pre-COVID-19 risk were women aged 35 upwards. We urgently need to quantify how much risk is due to COVID-19 infection and how much due to disruption to healthcare services to inform better shielding advice, prioritisation of healthcare services, and vaccine priorities for people with rare diseases.

18: The role of synovial T-cell infiltration following knee joint injury in symptoms and progression to osteoarthritis
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Posted 29 Nov 2019

The role of synovial T-cell infiltration following knee joint injury in symptoms and progression to osteoarthritis
640 downloads medRxiv rheumatology

Babak Moradi, Miriam T Jackson, Cindy C. Shu, Susan M Smith, Margaret M Smith, Sanaa Zaki, Hadrian Platzer, Nils Rosshirt, David Giangreco, Carla R Scanzello, Christopher B Little

ObjectivesIdentification of osteoarthritis(OA)-specific synovial inflammatory pathways, and when in the clinical course they are active, is critical for their utility as therapeutic targets. We directly compared the mononuclear inflammatory/immune-cell responses following joint injury that does and does-not lead to OA, to define bona-fide OA-associated cellular events. MethodsWe undertook detailed temporal flow-cytometric and mRNA expression analysis in mice after sham or medial-meniscal-destiblization (DMM) surgery. We compared this with patients with meniscal injury and OA, and evaluated the role of synovial monocytes/macrophages versus lymphocytes in catabolic metalloproteinase secrection in vitro. We determined the effect of transient acute or delayed systemic T-cell depletion on DMM-induced OA pathology. ResultsOA-inducing/DMM and non-OA-inducing/Sham surgery had identical synovial monocyte/macrophage number, activation and polarization. The number and activation of synovial (not splenic or peripheral-blood) CD4 and CD8 lymphocytes was increased from 1-day after DMM versus Sham, and showed a persistent cyclical elevation throughout OA onset and progression. There was a temporal imbalance in synovial Th17/Treg and Th1/Th2 lymphocytes during DMM-induced OA initiation and progression. We confirmed early post-injury and late-OA CD3/CD8 T-cell responses in synovial tissues from patients, identified an association between CD8 and early post-injury symptoms, and defined a significant role for CD3+T-cells in synovial metalloproteinase secretion. Anti-CD3 cell-depletion studies in mice confirmed a key role for the earliest post-injury T-cell response in long-term OA pathology. ConclusionsWe identify a hitherto unappreciated pathophysiological role of acute T-cell activation after joint injury in long-term post-traumatic OA risk, providing a novel diagnostic and therapeutic target. Key MessagesO_ST_ABSWhat is already known about this subject?C_ST_ABSThe presence of synovitis/joint-inflammation increases the risk not only of osteoarthritis (OA) progression but incident disease. While numerous inflammatory effectors including macrophages and lymphocytes have been identified in OA, their disease-specificity, temporal regulation, and association with risk of pathology onset and progression is lacking. How does this study add?By directly comparing the mononuclear inflammatory/immune-cell responses following significant joint injury that does (medial-meniscal-destabilization; DMM) and does-not (Sham-surgery) lead to OA in mice, we have defined bona-fide OA-associated cellular events. There was no difference in synovial or systemic monocyte/macrophage cell number, activation or polarization between DMM and Sham, both showing a successful wound-healing response. In contrast, increases in number and activation of synovial Th1- and Th17-CD4, and CD8 T-cells in DMM compared with Sham occurred within the first 3 days, and while recurring cyclically through subsequent disease onset, depletion studies indicated this initial influx was key to long-term ptOA risk. How might this impact on clinical practice of future developments?Acute increases in synovial T-cells following jont injury may be both a novel marker of OA risk, and a target to reduce long term structural damage.

19: A machine learning approach for precision diagnosis of juvenile-onset SLE
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Posted 05 Oct 2019

A machine learning approach for precision diagnosis of juvenile-onset SLE
613 downloads medRxiv rheumatology

George A Robinson, Junjie Peng, Pierre Dönnes, Leda Coelewij, Anna Radziszewska, Chris Wincup, Hannah Peckham, David A Isenberg, Yiannis Ioannou, Coziana Ciurtin, Ines Pineda-Torra, Elizabeth C Jury

Juvenile-Onset systemic lupus erythematosus (JSLE) is an autoimmune rheumatic disease characterised by systemic inflammation and organ damage, with disease onset often coinciding with puberty. JSLE is associated with more severe disease manifestations and a higher motility rate compared to adult SLE. Due to the heterogeneous clinical and immunological manifestations of JSLE, delayed diagnosis and poor treatment efficacy are major barriers for improving patient outcome. In order to define a unique immunophenotyping profile distinguishing JSLE patients from age matched healthy controls, immune-based machine learning (ML) approaches were applied. Balanced random forest analysis discriminated JSLE patients from healthy controls with an overall 91% prediction accuracy. The top-ranked immunological features were selected from the optimal ML model and were validated by partial least squares discriminant analysis and logistic regression analysis. Patients could be clustered into four distinct groups based on the top hits from the ML model, providing an opportunity for tailored therapy. Moreover, complex correlations between the JSLE immune profile and clinical features of disease were identified. Further immunological association studies are essential for developing data-driven personalised medicine approaches to aid diagnosis of JSLE for targeted therapy and improved patient outcomes.

20: Genome-wide reduction in chromatin accessibility and unique transcription factor footprints in endothelial cells and fibroblasts in scleroderma skin
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Posted 25 Jun 2020

Genome-wide reduction in chromatin accessibility and unique transcription factor footprints in endothelial cells and fibroblasts in scleroderma skin
580 downloads medRxiv rheumatology

Pei-Suen Tsou, Pamela J Palisoc, Mustafa Ali, Dinesh Khanna, Amr H Sawalha

Systemic sclerosis (SSc) is a rare autoimmune disease of unknown etiology characterized by widespread fibrosis and vascular complications. We utilized an assay for genome-wide chromatin accessibility to examine the chromatin landscape and transcription factor footprints in both endothelial cells (ECs) and fibroblasts isolated from healthy controls and patients with diffuse cutaneous (dc) SSc. In both cell types, chromatin accessibility was significantly reduced in SSc patients compared to healthy controls. Genes annotated from differentially accessible chromatin regions were enriched in pathways and gene ontologies involved in the nervous system. In addition, our data revealed that chromatin binding of transcription factors SNAI2, ETV2, and ELF1 was significantly increased in dcSSc ECs, while recruitment of RUNX1 and RUNX2 was enriched in dcSSc fibroblasts. Significant elevation of SNAI2 and ETV2 levels in dcSSc ECs, and RUNX2 levels in dcSSc fibroblasts were confirmed. Further analysis of publicly available ETV2-target genes suggests that ETV2 may play a critical role in EC dysfunction in dcSSc. Our data, for the first time, uncovered the chromatin blueprint of dcSSc ECs and fibroblasts, and suggested that neural-related characteristics of SSc ECs and fibroblasts could be a culprit for dysregulated angiogenesis and enhanced fibrosis. Targeting these pathways and the key transcription factors identified might present novel therapeutic approaches for this disease.

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