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    Frequency and severity of Covid-19 in patients treated with biological Disease MESHD Modifying Anti-Rheumatic Drugs (bDMARDs) for inflammatory rheumatic disease MESHD. A case-control study

    Authors: Dr. Anne LOHSE; Dr. Marie BOSSERT; Dr. Ana-Maria BOZGAN; Charlotte BOURGOIN; Dr. Aline CHARPENTIER; Dr. Cerise GUILLOCHON; Dr. Julie KESSLER; Dr. Jean-Charles BALBLANC; Dr. Thierry CONROZIER

    doi:10.21203/rs.3.rs-50490/v1 Date: 2020-07-29 Source: ResearchSquare

    The aim of the study was to assess the impact (frequency and severity) of Covid-19 on patients treated with biological Disease MESHD Modifying Anti-Rheumatic Drugs (bDMARDs) for inflammatory rheumatic disease MESHD and to compare it to a control group consisting of patients with musculoskeletal conditions not treated with bDMARDs.Patients and methods:A case control study in 200 outpatients with musculoskeletal conditions. 100 consecutive patients who have been treated with bDMARDs and 100 other consecutive patients who did not take bDMARDs were asked to complete a 15-item standardized questionnaire regarding demographic data. The following information was recorded: gender TRANS, age TRANS, weight, height, body mass index, professional activity, family status, total number of children TRANS and number of children TRANS under 18, rheumatic disease MESHD diagnosis, current treatment for rheumatism, type of containment, close contact TRANS with Covid-19 patients, Covid-19 symptoms, Covid-19 test result and hospitalization for Covid-19.Results:bDMARD patients mostly suffered from rheumatoid arthritis MESHD rheumatoid arthritis HP, or RA, (47%) and ankylosing spondylitis MESHD (42%). The most prescribed bDMARDs were TNFα inhibitors (57%), IL-6 blockers (12%) and JAK inhibitors (11%). The mean duration of the current biological treatment was 38.6 months. Patients from the control group were suffering chiefly from osteoarthritis MESHD osteoarthritis HP (45%) and RA (21%). Compared to the control group, patients treated with bDMARDs were 10 years younger (p<0.001), fewer were retired (56% versus 31%) and more were on sick or incapacity leave (6% versus 18%). During lockdown, they were more likely to be working from home or working short term (27% versus 9%). 18 patients from the bDMARDs group stopped biological treatment: one because of Covid-19 evidenced by PCR, 11 because of symptoms suggesting Covid- 19 and only six from fear of contracting the disease MESHD. 12 patients, including the one Sars-CoV-2 +, resumed their treatment after a few weeks of interruption. There was no severe Covid-19 infection MESHD in the bDMARDs group. Among the three patients from the control group who had contracted Covid-19, one developed a very severe disease MESHD.Conclusion :This case-control study did not show an increase in the frequency or severity of Covid-19 in subjects suffering from chronic inflammatory rheumatism treated with biotherapies. Larger-scale studies are necessary before affirming that biologics do not expose patients to an increased risk of disease MESHD and complications.

    COVID-19 and Rheumatoid Arthritis MESHD Rheumatoid Arthritis HP share myeloid pathogenic and resolving pathways

    Authors: Lucy MacDonald; Thomas Dan Otto; Aziza Elmesmari; Barbara Tolusso; Domenico Somma; Charles McSharry; Elisa Gremese; Iain B McInnes; Stefano Alivernini; Mariola Kurowska-Stolarska

    doi:10.1101/2020.07.26.221572 Date: 2020-07-26 Source: bioRxiv

    BackgroundWe recently delineated the functional biology of pathogenic and inflammation MESHD resolving synovial tissue macrophage clusters in rheumatoid arthritis MESHD rheumatoid arthritis HP (RA). Whilst RA is not a viral respiratory syndrome MESHD, it represents a pro-inflammatory cytokine-driven chronic articular condition often accompanied by cardiovascular and lung pathologies. We hypothesised that functionally equivalent macrophage clusters in the lung might govern inflammation MESHD and resolution of COVID-19 pneumonitis. MethodsTo provide insight into the targetable functions of COVID-19 bronchoalveolar lavage (BALF) macrophage clusters, a comparative analysis of BALF macrophage single cell transcriptomics (scRNA-seq) with synovial tissue (ST) macrophage scRNA-seq and functional biology was performed. The function of shared BALF and ST MerTK inflammation MESHD-resolving pathway was confirmed with inhibitor in primary macrophage-synovial fibroblast co-cultures. Results. Distinct BALF FCNpos and FCNposSPP1pos macrophage clusters emerging in severe COVID-19 patients were closely related to ST CD48highS100A12pos and CD48posSPP1pos clusters driving synovitis MESHD synovitis HP in active RA. They shared transcriptomic profile and pathogenic mechanisms. Healthy lung resident alveolar FABP4pos macrophages shared a regulatory transcriptomic profile, including TAM (Tyro, Axl, MerTK) receptors pathway with synovial tissue TREM2pos macrophages that govern RA remission. This pathway was substantially altered in BALF macrophages of severe COVID-19. In vitro dexamethasone inhibited tissue inflammation MESHD via macrophages MerTK function. ConclusionPathogenesis and resolution of COVID-19 pneumonitis and RA synovitis MESHD synovitis HP might be driven by similar macrophage clusters and pathways. The MerTK-dependent anti-inflammatory mechanisms of dexamethasone, and the homeostatic function of TAM pathways that maintain RA in remission advocate the therapeutic MerTK agonism to ameliorate the cytokine storm and pneumonitis of severe COVID-19.

    C-C chemokine receptor type 5 links COVID-19, Rheumatoid arthritis MESHD Rheumatoid arthritis HP, and Hydroxychloroquine

    Authors: Mahmood Yaseen Hachim; Ibrahim Hachim; Kashif Naeem; Haifa Hannawi; Issa Al Salmi; Suad Hannawi

    doi:10.21203/rs.3.rs-48001/v1 Date: 2020-07-23 Source: ResearchSquare

    Background: Patients with rheumatoid arthritis MESHD rheumatoid arthritis HP (RA) represent one of the fragile patient groups that might be susceptible to coronavirus disease MESHD -19 (COVID-19) and its severe form. On the other side, RA patients have been found not to have an increased risk of COVID19 infection MESHD. Moreover, some of the Disease MESHD-Modifying Anti-Rheumatic Drugs (DMARDS)  commonly used to treat rheumatic diseases MESHD like Hydroxychloroquine (HCQ) were proposed as a potential therapy for COVID19 with a lack of full understanding of their molecular mechanisms. This highlights the need for the discovery of common pathways that may link both diseases MESHD at the molecular side Methods: We used the in silico approach to investigate the transcriptomic profile of RA synovium compared to osteoarthritis MESHD osteoarthritis HP and healthy controls to identify RA specific molecular pathways shared with that of severe acute respiratory syndrome MESHD-corona virus-2 (SARS-COV-2) infected lung tissue. Results: Our results showed upregulation of chemotactic factors, including CCL4, CCL8, and CCL11, that all shared CCR5 as their receptor, as a common derangement observed in both diseases MESHD; RA and COVID-19. Moreover, our results also highlighted that HCQ might interfere with the COVID-19 infection MESHD through its ability to upregulate specific immune cell populations like activated natural killer (NK) cells, besides blocking CCR5 rich immune cell recruitment to the SARS-COV-2 infected lungs Conclusion: Our results might explain some of the reports that showed beneficial effects and indicate the need for proper patients stratification on their immune profile before selecting the therapeutic protocol or clinical trial enrollment. Keyword COVID-19, SARS-COV-2, Hydroxychloroquine, rheumatoid arthritis MESHD rheumatoid arthritis HP

    Transcriptional response modules characterise IL-1 and IL-6 activity in COVID-19

    Authors: Lucy C K Bell; Mahdad Noursadeghi; Gabriele Pollara

    doi:10.1101/2020.07.22.202275 Date: 2020-07-23 Source: bioRxiv

    Dysregulated IL-1 and IL-6 responses have been implicated in the pathogenesis of severe Coronavirus Disease MESHD 2019 (COVID-19). Innovative approaches for evaluating the biological activity of these cytokines in vivo are urgently needed to complement clinical trials of therapeutic targeting of IL-1 and IL-6 in COVID-19. We show that the expression of IL-1 or IL-6 inducible transcriptional signatures (modules) reflects the bioactivity of these cytokines in juvenile idiopathic arthritis MESHD arthritis HP (JIA) and rheumatoid arthritis MESHD rheumatoid arthritis HP, and discerns the effect of therapeutic cytokine blockade in JIA. In COVID-19, elevated expression of IL-1 and IL-6 response modules, but not these cytokines per se, is a feature of disease MESHD both in blood SERO and in affected organs. We propose that IL-1 and IL-6 transcriptional response modules can provide a dynamic readout of the activity of these cytokine pathways in vivo, with potential applications for identifying COVID-19 patients who may benefit from IL-1 or IL-6 blocking therapy, and to aid quantification of the biological effects of these treatments.

    Genetic inhibition of interleukin-6 receptor signaling and Covid-19

    Authors: Jonas Bovijn; Cecilia M. Lindgren; Michael V. Holmes

    doi:10.1101/2020.07.17.20155242 Date: 2020-07-19 Source: medRxiv

    There are few effective therapeutic options for the treatment of severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) infection MESHD. Early evidence has suggested that IL-6R blockers may confer benefit, particularly in severe coronavirus disease MESHD 2019 (Covid-19). We leveraged large-scale human genetic data to investigate whether IL6-R blockade may confer therapeutic benefit in Covid-19. A genetic instrument consisting of seven genetic variants in or close to IL6R was recently shown to be linked to altered levels of c-reactive protein (CRP), fibrinogen, circulating IL-6 and soluble IL-6R, concordant to known effects of pharmacological IL-6R blockade. We investigated the effect of these IL6R variants on risk of hospitalization for Covid-19 and other SARS-CoV-2-related outcomes using data from The Covid-19 Host Genetics Initiative. The IL6R variants were strongly associated with serum SERO CRP levels in UK Biobank. Meta-analysis of scaled estimates revealed a lower risk of rheumatoid arthritis MESHD rheumatoid arthritis HP (OR 0.93 per 0.1 SD lower CRP, 95% CI, 0.90-0.96, P = 9.5 x 10-7), recapitulating this established indication for IL-6R blockers (e.g. tocilizumab and sarilumab). The IL-6R instrument was associated with lower risk of hospitalization for Covid-19 (OR 0.88 per 0.1 SD lower CRP, 95% CI, 0.78-0.99, P = 0.03). We found a consistent association when using a population-based control group (i.e. all non-cases; OR 0.91 per 0.1 SD lower CRP, 95% CI, 0.87-0.96, P = 4.9 x 10-4). Evaluation of further SARS-CoV-2-related outcomes suggested association with risk of SARS-CoV-2 infection MESHD, with no evidence of association with Covid-19 complicated by death MESHD or requiring respiratory support. We performed several sensitivity SERO analyses to evaluate the robustness of our findings. Our results serve as genetic evidence for the potential efficacy of IL-6R blockade in Covid-19. Ongoing large-scale RCTs of IL-6R blockers will be instrumental in identifying the settings, including stage of disease MESHD, in which these agents may be effective.

    Calming the Cytokine Storm - Splenic Ultrasound for Treating Inflammatory Disorders and Potentially COVID-19

    Authors: 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

    doi:10.1101/2020.07.14.20153528 Date: 2020-07-17 Source: medRxiv

    Hyperinflammation and uncontrolled cytokine release, which can be seen in severe cases of COVID-19, require therapy to reduce the innate immune response without hindering necessary adaptive immune mechanisms. Here, we show results from the first in-human trials using non-invasive ultrasound stimulation of the spleen to reduce cytokine release in the context of both an acute response in healthy subjects and a chronic inflammatory condition in rheumatoid arthritis MESHD rheumatoid arthritis HP patients. Splenic ultrasound results in a reduction in TNF serum SERO levels, as well as IL-1B; and IL-8 transcript levels in monocytes. There is also a down regulation of pathways involved in TNF and IL-6 production, and IFNgamma- and NFKB-regulated genes. Many of these cytokines or pathways are upregulated in COVID-19 patients. There is also a reduction in chemokine transcript levels and other components of the chemotactic response, suggesting that reduction of cellular migration may contribute to the therapeutic effects of ultrasound. There is no inhibition of the adaptive immune response with ultrasound treatment relating to antibody SERO production. This is consistent with a pre-clinical animal model where enhanced antibody SERO production was achieved with splenic ultrasound. Therefore, this new splenic ultrasound approach has the potential to treat acute and chronic hyper-inflammatory diseases MESHD, as it lowers cytokine levels without disrupting the normal adaptive immune response. Portable ultrasound technologies are currently being developed and translated to the clinic to treat various inflammatory disorders, with more recent efforts directed towards combatting the hyperinflammation or cytokine storm in COVID-19 patients.

    The effect of hydroxychloroquine against SARS-CoV-2 infection MESHD in rheumatoid arthritis MESHD rheumatoid arthritis HP patients

    Authors: Okan Küçükakkaş; Teoman Aydın

    doi:10.21203/rs.3.rs-43812/v1 Date: 2020-07-15 Source: ResearchSquare

    INTRODUCTION: The effectiveness of hydroxychloroquine in SARS-CoV-2 prophylaxis and treatment is still controversial. In this study, our aim is to investigate the potential effects of hydroxychloroquine therapy on patients with diagnosed with rheumatoid arthritis MESHD rheumatoid arthritis HP and a confirmed SARS-CoV-2 infection MESHD.METHOD: We included patients who were followed up with a diagnosis of rheumatoid arthritis MESHD rheumatoid arthritis HP and whose SARS-CoV-2 infection MESHD infection was confirmed TRANS was confirmed. The patients were divided into two groups as those who previously used hydroxychloroquine and those who did not, and were compared in terms of clinical and laboratory data.RESULTS: Our study included 17 patients with adequate data (2 males TRANS, 15 females TRANS). The mean age TRANS of the patients was 57.2 ± 11.6 years. 7 (41.2%) patients were receiving hydroxychloroquine regularly for the last 6 months. When the effect of hydroxychloroquine on clinical and laboratory parameters of patients was examined, there was no significant difference between the groups of patients using and not using hydroxychloroquine. The patients using and not using hydroxychloroquine were compared for the presence of typical SARS-CoV-2 infection MESHD findings on computed tomography images, admission to the hospital and intensive care. No significant differences were observed between these two groups.CONCLUSIONS: Many studies on the effectiveness of hydroxychloroquine use in SARS-CoV-2 infection MESHD are still ongoing. Due to its importance in rheumatology practice, it is very important to clarify the position of hydroxychloroquine in SARS-CoV-2 therapy. Our findings suggest that having previously used hydroxychloroquine does not have any negative or positive effect on the infection MESHD.

    Successful management of a case of SARS‐CoV‐2 infection MESHD in an advanced Rheumatoid Arthritis MESHD Rheumatoid Arthritis HP patient by dose reduction of immunosuppressive medication

    Authors: Ahmadreza Bazmjoo; Mohammad Aref Bagherzadeh; Farida Farahmandpoor; Rahim Raoofi; Amir Abdoli

    doi:10.21203/rs.3.rs-40731/v1 Date: 2020-07-08 Source: ResearchSquare

    Rheumatoid Arthritis MESHD Rheumatoid Arthritis HP (RA) patients usually managed with immunosuppressive agents and they are at a higher risk of infections TRANS risk of infections TRANS infections MESHD. There are limited data regarding RA patients with COVID-19. This article reports a RA patient with an acute SARS‐CoV‐2 infection MESHD that successfully managed by dose reduction of immunosuppressive medication.

    Chronic treatment with hydroxychloroquine and SARS-CoV-2 infection MESHD.

    Authors: Antonio Ferreira; Antonio Oliveira-e-Silva; Paulo Bettencourt

    doi:10.1101/2020.06.26.20056507 Date: 2020-06-29 Source: medRxiv

    Background: Hydroxychloroquine sulphate (HCQ) is being scrutinized for repositioning in the treatment and prevention of SARS-Cov-2 infection MESHD. This antimalarial drug is also chronically used to treat patients with autoimmune diseases MESHD. Methods: By analyzing the Portuguese anonymized data on private and public based medical prescriptions we have identified all cases chronically receiving HCQ for the management of diseases MESHD such as systemic lupus erythematosus MESHD systemic lupus erythematosus HP, rheumatoid arthritis MESHD rheumatoid arthritis HP, and other autoimmune diseases MESHD. Additionally, we have detected all laboratory confirmed cases TRANS of SARS-CoV-2 infection and all laboratory MESHD confirmed negative cases in the Portuguese population (mandatorily registered in a centrally managed database). Cross linking the two sets of data has allowed us to compare the proportion of HCQ chronic treatment (at least 2 grams per month) in laboratory confirmed cases TRANS of SARS-CoV-2 infection with laboratory MESHD confirmed negative cases. Results: Out of 26,815 SARS-CoV-2 positive patients, 77 (0.29%) were chronically treated with HCQ, while 1,215 (0.36%) out of 333,489 negative patients were receiving it chronically (P=0.04). After adjustment for age TRANS, sex, and chronic treatment with corticosteroids and/or immunosuppressants, the odds ratio of SARS-CoV-2 infection MESHD infection for chronic HP for chronic treatment with HCQ has been 0.51 (0.37-0.70). Conclusions: Our data suggest that chronic treatment with HCQ confer protection against SARS-CoV-2 infection MESHD.

    Does Biological Therapy Protect against Severe COVID-19?

    Authors: 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

    doi:10.1101/2020.06.21.20136788 Date: 2020-06-24 Source: medRxiv

    Objective. To estimate COVID-19 infection MESHD incidence rate with severe affectation (requiring hospitalization) in patients with biological treatment due to rheumatoid arthritis MESHD rheumatoid arthritis HP (RA), psoriatic arthritis MESHD arthritis HP (PsA), spondyloarthritis (SpA), psoriasis MESHD (Ps), and inflammatory bowel disease MESHD (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 MESHD 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 TRANS 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 TRANS 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.

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