Pathophysiology of acute respiratory syndrome coronavirus 2 infection: a systematic literature review to inform EULAR points to consider

BackgroundThe SARS-CoV-2 pandemic is a global health problem. Beside the specific pathogenic effect of SARS-CoV-2, incompletely understood deleterious and aberrant host immune responses play critical roles in severe disease. Our objective was to summarise the available information on the pathophysiology of COVID-19.MethodsTwo reviewers independently identified eligible studies according to the following PICO framework: P (population): patients with SARS-CoV-2 infection; I (intervention): any intervention/no intervention; C (comparator): any comparator; O (outcome) any clinical or serological outcome including but not limited to immune cell phenotype and function and serum cytokine concentration.ResultsOf the 55 496 records yielded, 84 articles were eligible for inclusion according to question-specific research criteria. Proinflammatory cytokine expression, including interleukin-6 (IL-6), was increased, especially in severe COVID-19, although not as high as other states with severe systemic inflammation. The myeloid and lymphoid compartments were differentially affected by SARS-CoV-2 infection depending on disease phenotype. Failure to maintain high interferon (IFN) levels was characteristic of severe forms of COVID-19 and could be related to loss-of-function mutations in the IFN pathway and/or the presence of anti-IFN antibodies. Antibody response to SARS-CoV-2 infection showed a high variability across individuals and disease spectrum. Multiparametric algorithms showed variable diagnostic performances in predicting survival, hospitalisation, disease progression or severity, and mortality.ConclusionsSARS-CoV-2 infection affects both humoral and cellular immunity depending on both disease severity and individual parameters. This systematic literature review informed the EULAR ‘points to consider’ on COVID-19 pathophysiology and immunomodulatory therapies.

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POS0052 PATHOPHYSIOLOGY OF ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 INFECTION: A SYSTEMATIC LITERATURE REVIEW TO INFORM EULAR POINTS TO CONSIDER

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2851 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 231-232

Author(s):

A. Najm ◽

A. Alunno ◽

X. Mariette ◽

B. Terrier ◽

G. De Marco ◽

...

Keyword(s):

Immune Responses ◽

Immune Cell ◽

Research Question ◽

Severe Disease ◽

Cell Number ◽

Cell Phenotype ◽

Host Immune Responses ◽

Disease Spectrum ◽

And Function ◽

Immunomodulatory Therapies

Background:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a global health problem. Beside the specific pathogenic effect of SARS-CoV-2, incompletely understood deleterious and aberrant host immune responses play critical roles in severe disease. Rheumatologists have the best experience of studying and treating these complicated hyperinflammatory processes.Objectives:To summarize the available information on pathophysiology of COVID-19.Methods:As part of a EULAR taskforce, two systematic literature reviews were performed one on pathophysiology and one on immunomodulatory therapies. Two reviewers independently identified eligible studies according to the following PICO framework: P (population): patients with SARS-CoV-2 infection; I (intervention): any intervention/no intervention; C (comparator): any comparator; O (outcome) any clinical or serological outcome including but not limited to immune cell phenotype and function and serum cytokine concentration. The results pertaining to pathophysiology of COVID-19 are presented here.Results:Of the 55496 records yielded, 85 articles were eligible for inclusion. Included studies were at variable risk of bias and exploring various aspects of disease pathogenesis from immune to non-immune cells (Table 1). Pro-inflammatory cytokines’ expression including IL-6, was increased, especially in severe COVID-19, although not as high as other states with severe systemic inflammation. Innate and adaptative immune cell compartments were differentially affected by SARS-CoV-2 infection: neutrophils displayed an immature differentiation state and also increased neutrophil extracellular traps (NETs) formation. Dendritic cell number was reduced and classical monocytes was increased although displaying a reduced expression of HLA-DR. The lymphoid compartment was also affected: lymphopenia was present with a reduced number of CD4+ and CD8+ T lymphocytes and more frequent PD1+CD8+ T cells corresponding to an exhausted phenotype. Antibody response to SARS-CoV-2 infection showed a high variability across individuals and disease spectrum. Multiparametric algorithms showed variable diagnostic performances in predicting survival, hospitalization, disease progression or severity, and mortality. Differences in SARS-CoV-2 manifestations in adults and children were highlighted.Conclusion:Overall, SARS-CoV-2 infection affects both innate and adaptative immune responses in a variable way, according to both disease severity and individual parameters. This SLR informs the EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19.Table 1.Studies on SARS-CoV-2 infection pathogenesisResearch questionNCytokines profile7Immune profile18Algorithm17Children3Comorbidities1Endothelial dysfunction and platelets8Gut and microbiota3Genetics and variants8Histology7Antibodies profiles8Viral load and immune response4Interferon3Immunosenecsnce3Total90**Some manuscripts were including in several research questions. Total number of studies included n=85.Disclosure of Interests:Aurelie Najm Speakers bureau: BMS, Consultant of: BMS, Alessia Alunno: None declared, Xavier Mariette Speakers bureau: BMS, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Servier and UCB, Consultant of: BMS, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Servier and UCB, Benjamin Terrier Speakers bureau: Roche, Chugai, Vifor Pharma, GSK, AstraZeneca, Terumo BCT, LFB and Grifols, Consultant of: Roche, Chugai, Vifor Pharma, GSK, AstraZeneca, Terumo BCT, LFB and Grifols, Gabriele De Marco: None declared, Laura Mason: None declared, Jenny Emmel: None declared, Dennis McGonagle Speakers bureau: Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, Consultant of: Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, Pedro M Machado Speakers bureau: Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, Consultant of: Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB.

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AB0602 IMPACT OF SOCIOECONOMIC FACTORS ON PAIN AND FUNCTION IN KNEE OSTEOARTHRITIS: A SYSTEMATIC LITERATURE REVIEW

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3634 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1337.2-1337

Author(s):

T. W. Swinnen ◽

M. Willems ◽

I. Jonkers ◽

F. P. Luyten ◽

J. Vanrenterghem ◽

...

Keyword(s):

Risk Factors ◽

Literature Review ◽

Knee Osteoarthritis ◽

Socioeconomic Factors ◽

Systematic Literature Review ◽

Intervention Effects ◽

Socioeconomic Outcomes ◽

And Function ◽

The Impact

Background:The personal and societal burden of knee osteoarthritis (KOA) urges the research community to identify factors that predict its onset and progression. A mechanistic understanding of disease is currently lacking but needed to develop targeted interventions. Traditionally, risk factors for KOA are termed ‘local’ to the joint or ‘systemic’ referring to whole-body systems. There are however clear indications in the scientific literature that contextual factors such as socioeconomic position merit further scientific scrutiny, in order to justify a more biopsychosocial view on risk factors in KOA.Objectives:The aims of this systematic literature review were to assess the inclusion of socioeconomic factors in KOA research and to identify the impact of socioeconomic factors on pain and function in KOA.Methods:Major bibliographic databases, namely Medline, Embase, CINAHL, Web of Science and Cochrane, were independently screened by two reviewers (plus one to resolve conflicts) to identify research articles dealing with socioeconomic factors in the KOA population without arthroplasty. Included studies had to quantify the relationship between socioeconomic factors and pain or function. Main exclusion criteria were: a qualitative design, subject age below 16 years and articles not written in English or Dutch. Methodological quality was assessed via the Cochrane risk of bias tools for randomized (ROB-II) and non-randomized intervention studies (ROBIN-I) and the Newcastle-Ottawa Scale for assessing the quality of non-randomised studies. Due to heterogeneity of studies with respect to outcomes assessed and analyses performed, no meta-analysis was performed.Results:Following de-duplication, 7639 articles were available for screening (120 conflicts resolved without a third reader). In 4112 articles, the KOA population was confirmed. 1906 (25%) were excluded because of knee arthroplasty and 1621 (21%) because of other issues related to the population definition. Socioeconomic factors could not be identified in 4058 (53%) papers and were adjusted for in 211 (3%) articles. In the remaining papers covering pain (n=110) and/or function (n=81), education (62%) and race (37%) were most frequently assessed as socioeconomic factors. A huge variety of mainly dichotomous or ordinal socioeconomic outcomes was found without further methodological justification nor sensitivity analysis to unravel the impact of selected categories. Although the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was the most popular instrument to assess pain and function, data pooling was not possible as socioeconomic factors estimates were part of multilevel models in most studies. Overall results showed that lower education and African American race were consistent predictors of pain and poor function, but those effects diminished or disappeared when psychological aspects (e.g. discrimination) or poverty estimates were taken into account. When function was assessed using self-reported outcomes, the impact of socioeconomic factors was more clear versus performance-based instruments. Quality of research was low to moderate and the moderating or mediating impact of socioeconomic factors on intervention effects in KOA is understudied.Conclusion:Research on contextual socioeconomic factors in KOA is insufficiently addressed and their assessment is highly variable methodologically. Following this systematic literature review, we can highlight the importance of implementing a standardised and feasible set of socioeconomic outcomes in KOA trials1, as well as the importance of public availability of research databases including these factors. Future research should prioritise the underlying mechanisms in the effect of especially education and race on pain and function and assess its impact on intervention effects to fuel novel (non-)pharmacological approaches in KOA.References:[1]Smith TO et al. The OMERACT-OARSI Core Domain Set for Measurement in Clinical Trials of Hip and/or Knee Osteoarthritis J Rheumatol 2019. 46:981–9.Disclosure of Interests:None declared.

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Sex differences in autoimmunity could be associated with altered regulatory T cell phenotype and lipoprotein metabolism

10.1101/760975 ◽

2019 ◽

Author(s):

George A Robinson ◽

Kirsty E Waddington ◽

Marsilio Adriani ◽

Anna Radziszewska ◽

Hannah Peckham ◽

...

Keyword(s):

Sex Differences ◽

T Cell ◽

Regulatory T Cell ◽

Immune Cell ◽

Pubertal Development ◽

Cell Subset ◽

Cell Phenotype ◽

Healthy Adolescent ◽

Treg Frequency ◽

And Function

ABSTRACTMale and female immune responses are known to differ resulting in an increased prevalence of autoimmunity in women. Here sex differences in T-cell subset frequency and function during adolescence were examined in healthy donors and patients with the autoimmune disease juvenile (J)SLE; onset of JSLE commonly occurs during puberty suggesting a strong hormonal influence. Healthy adolescent males had increased regulatory T-cell (Treg) frequency, and increased Treg suppressive capacity and IL-4 production compared to healthy adolescent females. The T-helper 2-like profile in male Tregs was associated with increased expression of GATA3 which correlated significantly with elevated Treg plasma membrane glycosphingolipid expression. Differential Treg phenotype was associated with unique serum metabolomic profiles in males compared to female adolescents. Notably, very low density lipoprotein (VLDL) metabolomic signatures correlated positively with activated Tregs in males but with resting Tregs in females. Consistently, only VLDL isolated from male serum was able to induce increased Treg IL-4 production and glycosphingolipid expression following in cultured cells. Remarkably, gender differences in Treg frequency, phenotype and function and serum metabolomic profiles were lost in adolescents with JSLE. This work provides evidence that a combination of pubertal development, immune cell defects and dyslipidemia may contribute to JSLE pathogenesis.

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Genes Whose Gain or Loss-of-Function Increases Endurance Performance in Mice: A Systematic Literature Review

Frontiers in Physiology ◽

10.3389/fphys.2019.00262 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 2

Author(s):

Fakhreddin Yaghoob Nezhad ◽

Sander A. J. Verbrugge ◽

Martin Schönfelder ◽

Lore Becker ◽

Martin Hrabě de Angelis ◽

...

Keyword(s):

Literature Review ◽

Systematic Literature Review ◽

Endurance Performance ◽

Loss Of Function

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(434) Pain and function in head and neck cancer: a systematic literature review

Journal of Pain ◽

10.1016/j.jpain.2017.02.284 ◽

2017 ◽

Vol 18 (4) ◽

pp. S82

Author(s):

J. Van Cleave ◽

C. DiMaria ◽

S. DiMaria ◽

E. Liang ◽

C. Long ◽

...

Keyword(s):

Head And Neck Cancer ◽

Literature Review ◽

Head And Neck ◽

Neck Cancer ◽

Systematic Literature Review ◽

And Function

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Outcome measures and their measurement properties for trapeziometacarpal osteoarthritis: a systematic literature review

Journal of Hand Surgery (European Volume) ◽

10.1177/1753193413488301 ◽

2013 ◽

Vol 38 (8) ◽

pp. 822-838 ◽

Cited By ~ 27

Author(s):

M. Marks ◽

J. W. Schoones ◽

C. Kolling ◽

D. B. Herren ◽

J. Goldhahn ◽

...

Keyword(s):

Literature Review ◽

Outcome Measures ◽

Systematic Literature Review ◽

Global Assessment ◽

Measurement Properties ◽

Five Dimensions ◽

Trapeziometacarpal Osteoarthritis ◽

Core Set ◽

And Function

The objective was to identify all outcome measures used in studies on trapeziometacarpal osteoarthritis (TMC OA) and evaluate their measurement properties. In a two-step systematic literature review, we first identified studies including TMC OA patients and extracted all outcome measures. They were categorized according to the Outcome Measures in Rheumatology (OMERACT) core set for OA including five dimensions: pain, physical function, global assessment, imaging, and quality of life (QoL). Secondly, we retrieved articles on the measurement properties of the identified outcome measures for TMC OA patients. First, 316 articles including 101 different outcome measures were identified, addressing the OMERACT pain and function domains most frequently but under-representing QoL. Second, 12 articles investigating measurement properties of 12 outcome measures were identified. The methodological quality of these studies was poor to fair, implying that based on the literature no recommendations to use any of the outcome measures can yet be made.

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MicroRNA-155 Regulates MAIT1 and MAIT17 Cell Differentiation

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.670531 ◽

2021 ◽

Vol 9 ◽

Author(s):

Tingting Liu ◽

Jie Wang ◽

Kalpana Subedi ◽

Qijun Yi ◽

Li Zhou ◽

...

Keyword(s):

Immune Cell ◽

Cell Lineage ◽

Cell Development ◽

Loss Of Function ◽

Mait Cells ◽

Cellular Processes ◽

Individual Mirnas ◽

Maturation Stages ◽

And Function ◽

Mait Cell

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that develop in the thymus through three maturation stages to acquire effector function and differentiate into MAIT1 (T-bet+) and MAIT17 (RORγt+) subsets. Upon activation, MAIT cells release IFN-γ and IL-17, which modulate a broad spectrum of diseases. Recent studies indicate defective MAIT cell development in microRNA deficient mice, however, few individual miRNAs have been identified to regulate MAIT cells. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affect some immune cell development, but its role in MAIT cell development remains unclear. To address whether miR-155 is required for MAIT cell development, we performed gain-of-function and loss-of-function studies. We first generated a CD4Cre.miR-155 knock-in mouse model, in which miR-155 is over-expressed in the T cell lineage. We found that overexpression of miR-155 significantly reduced numbers and frequencies of MAIT cells in all immune organs and lungs and blocked thymic MAIT cell maturation through downregulating PLZF expression. Strikingly, upregulated miR-155 promoted MAIT1 differentiation and blocked MAIT17 differentiation, and timely inducible expression of miR-155 functionally inhibited peripheral MAIT cells secreting IL-17. miR-155 overexpression also increased CD4–CD8+ subset and decreased CD4–CD8– subset of MAIT cells. We further analyzed MAIT cells in conventional miR-155 knockout mice and found that lack of miR-155 also promoted MAIT1 differentiation and blocked MAIT17 differentiation but without alteration of their overall frequency, maturation and function. Overall, our results indicate that adequate miR-155 expression is required for normal MAIT1 and MAIT17 cell development and function.

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