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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
35,367 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 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.
7,030 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: Recommendations for COVID-19 Vaccination in People with Rheumatic Disease: Developed by the Singapore Chapter of Rheumatologists
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Posted 08 Mar 2021

Recommendations for COVID-19 Vaccination in People with Rheumatic Disease: Developed by the Singapore Chapter of Rheumatologists
3,179 downloads medRxiv rheumatology

Amelia Santosa, Chuanhui Xu, Thaschawee Arkachaisri, Kok Ooi Kong, Aisha Lateef, Tau Hong Lee, Keng Hong Leong, Andrea HL Low, Melonie K Sriranganathan, Teck Choon Tan, Gim Gee Teng, Bernard Y Thong, Warren Fong, Manjari Lahiri

AimPeople with rheumatic diseases (PRD) remain vulnerable in the era of the COVID-19 pandemic. We formulated recommendations to meet the urgent need for a consensus for vaccination against SARS-CoV-2 in PRD. MethodsSystematic literature reviews were performed to evaluate (1) outcomes in PRD with COVID-19; (2) efficacy, immunogenicity and safety of COVID-19 vaccination; and (3) published guidelines/recommendations for non-live, non-COVID-19 vaccinations in PRD. Recommendations were formulated based on the evidence and expert opinion according to the Grading of Recommendations Assessment, Development and Evaluation methodology. ResultsThe consensus comprises two overarching principles and seven recommendations. Vaccination against SARS-CoV-2 in PRD should be aligned with prevailing national policy and should be individualized through shared decision between the healthcare provider and patient. We strongly recommended that eligible PRD and household contacts be vaccinated against SARS-CoV-2. We conditionally recommended that the COVID-19 vaccine be administered during quiescent disease if possible. Immunomodulatory drugs, other than rituximab, can be continued alongside vaccination. We conditionally recommended that the COVID-19 vaccine be administered prior to commencing rituximab if possible. For patients on rituximab, the vaccine should be administered a minimum of 6 months after the last dose and/or 4 weeks prior to the next dose of rituximab. Post-vaccination antibody titres against SARS-CoV-2 need not be measured. Any of the approved COVID-19 vaccines may be used, with no particular preference. ConclusionThese recommendations provide guidance for COVID-19 vaccination in PRD. Most recommendations in this consensus are conditional, reflecting a lack of evidence or low-level evidence.

4: 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
2,003 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.

5: 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
1,604 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

6: Methotrexate Hampers Immunogenicity to BNT162b2 mRNA COVID-19 Vaccine in Immune-Mediated Inflammatory Disease
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Posted 12 May 2021

Methotrexate Hampers Immunogenicity to BNT162b2 mRNA COVID-19 Vaccine in Immune-Mediated Inflammatory Disease
1,508 downloads medRxiv rheumatology

Rebecca H Haberman, Ramin Herati, David Simon, Marie Samanovic, Rebecca B. Blank, Michael Tuen, Sergei Koralov, Raja Atreya, Koray Tascilar, Joseph Allen, Rochelle Castillo, Amber Cornelius, Paula Rackoff, Gary Solomon, Samrachana Adhikari, Natalie Azar, Pamela Rosenthal, Peter Izmirly, Jonathan Samuels, Brian Golden, Soumya Reddy, Markus F. Neurath, Steven B. Abramson, Georg Schett, Mark J Mulligan, Jose U Scher

Objective: To investigate the humoral and cellular immune response to mRNA COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment. Methods: Established patients at NYU Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunization. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analyzed for humoral response. Cellular immune response to SARS-CoV-2 was further analyzed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany were also analyzed for humoral immune response. Results: Although healthy subjects (n=208) and IMID patients on biologic treatments (mostly on TNF blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, IMID patients do not demonstrate an increase in CD8+ T cell activation after vaccination. Conclusions: In two independent cohorts of IMID patients, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunization efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines.

7: 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
1,208 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.

8: 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
1,145 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.

9: 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
1,136 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.

10: 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.
938 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.

11: Humoral response to Pfizer mRNA vaccine against SARS CoV2, in patients with autoimmune inflammatory rheumatic diseases and the impact on the rheumatic disease activity
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Posted 06 Apr 2021

Humoral response to Pfizer mRNA vaccine against SARS CoV2, in patients with autoimmune inflammatory rheumatic diseases and the impact on the rheumatic disease activity
928 downloads medRxiv rheumatology

Yolanda Braun-Moscovici, Marielle Kaplan, Doron Markovits, Samy Giryes, Kochava Toledano, Yonit Tavor, Katya Dolnikov, Alexandra Balbir-Gurman

Abstract Background: The registration trials of mRNA vaccines against SARS CoV2 did not address patients with autoimmune inflammatory rheumatoid diseases (AIRD). Aims: To assess the humoral response to mRNA vaccine against SARS CoV2, in AIRD patients treated with immunomodulating drugs and the impact on AIRD activity. Methods: Consecutive patients treated at the rheumatology institute who received their first SARS-CoV-2 (Pfizer) vaccine were recruited to the study, at their routine visit. The patients were invited for serology test 4-6 weeks after receiving the second dose of vaccine. IgG Antibodies (Ab) against SARS COV2 virus were detected using the SARS-Cov-2 IgG II Quant (Abbott) assay Results: One hundred fifty-six consecutive patients (76% females) treated at a single rheumatology center (mean age (range) 59.1 (21-83) years), mean (range) disease duration 10.8 (1-55) years), were recruited to the study. Thirty-five percents of patients received conventional synthetic (cs)DMARDs only, 64% biological/targeted synthetic (b/ts) DMARDs, 34% received combined treatment with csDMARDs and b/tsDMARDs and 32% corticosteroids (mean dose(range) 5.8mg(2.5-20mg) prednisone). One hundred thirty-seven patients (88%) were seropositive for IgG Ab against SARS CoV2 virus (median 2832.5 AU/ml, range 58-29499). Nineteen (12%) patients had negative tests, 11/19 were treated with B cell depleting agents. The reported side effects of the vaccine were minor (muscle sore, headache, low grade fever). The rheumatic disease remained stable in all patients. Conclusions: The vast majority of AIRD patients developed a significant humoral response following the administration of the second dose of the Pfeizer mRNA vaccine against SARS CoV2 virus. Only minor side effects were reported and no apparent impact on AIRD activity was noted.

12: 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
927 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.

13: Immunogenicity of the ChAdOx1 nCoV-19 and the BBV152 Vaccines in Patients with Autoimmune Rheumatic Diseases
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Posted 07 Jun 2021

Immunogenicity of the ChAdOx1 nCoV-19 and the BBV152 Vaccines in Patients with Autoimmune Rheumatic Diseases
924 downloads medRxiv rheumatology

Padmanbha Shenoy, Sakir Ahmed, Somy Cherin, Aby Paul, Veena Shenoy, Anuroopa Vijayan, Reshma Reji, Arya Thampi, Sageer Babu AS, Manju Mohan

Introduction: There is limited information on the effectiveness of COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD). Methods: 136 consecutive patients with rheumatic diseases who never had a diagnosis of COVID-19 previously, and had completed vaccination with either the ChAdOx1 or BBV152 vaccines were recruited. Their IgG antibody titres to the Spike protein were estimated 1 month after the second dose. Results: 102 patients had AIRD while the 34 had non-AIRD. Lesser patients with AIRD (92/102) had positive antibodies titres than ones with non-AIRD(33/34) [p<0.001]. Amongst patients who received the ChAdOX1 vaccine, the AIRD group had lower antibody titres. Although the AIRD patients receiving BBV152 had similarly lower titres numerically, this did not attain statistical significance probably due to lesser numbers. Comparing the two vaccines, 114(95%) of those who received ChAdOx1 (n=120) and 11(68.7%) of those who received BBV152(n=16) had detectable antibodies [p=0.004] . Antibody titres also were higher in ChAdOx1 recipients when compared to BBV152. To validate the findings, we estimated antibody titres in 30 healthy people each who had received either vaccine. All 30 who had received ChAdOX1 and only 23/30 of those who had received BBV152 had positive antibodies (p=0.011). Conclusion: In this preliminary analysis, patients with AIRD had lower seroconversion rates as well as lower antibody titres as compared to patients with non-AIRD. Also,the humoral immunogenicity of the BBV152 vaccine appears to be less than that of the ChAdOX1 vaccine. Validation using larger numbers and testing of cellular immunity is urgently required.

14: 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
909 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.

15: 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
887 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.

16: 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
871 downloads medRxiv rheumatology

Vivian E. Saper, Guangbo Chen, Gail Deutsch, R Paul. Guillerman, Johannes Birgmeier, Karthik A. Jagadeesh, Scott W. 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.

17: 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
851 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.

18: Association between anti-interferon-alpha autoantibodies and COVID-19 in systemic lupus erythematosus
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Posted 03 Nov 2020

Association between anti-interferon-alpha autoantibodies and COVID-19 in systemic lupus erythematosus
850 downloads medRxiv rheumatology

Sarthak Gupta, Shuichiro Nakabo, Jun Chu, Sarfaraz Hasni, Mariana J. Kaplan

ObjectivesAnti-type I interferon (IFN) autoantibodies have been reported in patients with systemic lupus erythematosus (SLE). Recently, an association of these autoantibodies with severe COVID-19 was reported in the general population. We assessed whether having pre-existing anti-IFN autoantibodies was associated with COVID-19 infection in SLE patients. MethodsPatients with SLE who developed COVID-19 between April 1st to October 1st, 2020 were studied. Biobanked pre-COVID-19 plasma from these SLE subjects and healthy controls were tested for anti-IFN IgG autoantibodies by ELISA. The ability of plasma anti-IFN autoantibodies to block signal transducer and activator of transcription 1 (STAT1) phosphorylation by recombinant human IFN in vitro was assessed by flow cytometry. ResultsTen SLE subjects with COVID-19 were identified. A 40% of these subjects had stable autoantibodies against IFN for up to three years preceding COVID-19 diagnosis. A 50% of the subjects with these autoantibodies neutralized IFN induced STAT1 phosphorylation.None of the other SLE samples blocked IFN signaling. ConclusionsWe noted an increased prevalence of pre-existing anti-IFN autoantibodies in SLE patients with COVID-19 compared to the reported prevalence in lupus patients and the general population with severe COVID-19. Autoantibodies against IFN in SLE patients may be pathogenic and patients with them maybe at-risk of developing COVID-19. Key MessagesO_ST_ABSWhat is already known about this subject?C_ST_ABS- Anti-type I interferon (IFN) autoantibodies have been reported in patients with systemic lupus erythematosus (SLE) and have recently been associated with severe COVID-19 in the general population. What does this study add?- SLE subjects with COVID-19 had an increased prevalence of pre-existing anti-IFN autoantibodies compared to the reported prevalence in lupus patients and the general population with severe COVID-19. - Plasma from 50% of subjects with these autoantibodies were able to block in vitro activity of IFN. - SLE patients with pre-existing anti-IFN autoantibodies had more severe COVID-19 manifestations. How might this impact on clinical practice or future developments?- Anti-IFN autoantibodies may be pathogenic and could prove to be a helpful prognostic marker to predict which SLE patient may develop COVID-19 and inform preventive measures and management of this subset of patients.

19: 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
823 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 dos 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.

20: 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
773 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

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