Nature Reviews Rheumatology

Fatigue is a complex phenomenon and an important health concern for many people with chronic inflammatory rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, primary Sjögren syndrome and systemic lupus erythematosus. Although some clinical trials have shown the benefits of cognitive behavioural therapy in fatigue management, the effect of this approach is relatively modest, and no curative treatment has been identified. The pathogenesis of fatigue remains unclear. Despite many challenges and limitations, a growing body of research points to roles for the immune system, the central and autonomic nervous systems and the neuroendocrine system in the induction and maintenance of fatigue in chronic diseases. New insights indicate that sleep, genetic susceptibility, metabolic disturbances and other biological and physiological mechanisms contribute to fatigue. Furthermore, understanding of the relationships between psychosocial factors and fatigue is increasing. However, the interrelationships between these diverse mechanisms and fatigue remain poorly defined. In this Review, we outline various biological, physiological and psychosocial determinants of fatigue in inflammatory rheumatic diseases, and propose mechanistic and conceptual models of fatigue to summarize current understanding, stimulate debate and develop further research ideas.

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Detection of microvascular changes in systemic sclerosis and other rheumatic diseases

Maurizio Cutolo & Vanessa Smith

doi : 10.1038/s41584-021-00685-0

Nature Reviews Rheumatology volume 17, pages665–677 (2021)

Morphological and functional analysis of the microcirculation are objective outcome measures that are recommended for use in the presence of clinical signs of altered peripheral blood flow (such as Raynaud phenomenon), which can occur in systemic sclerosis (SSc) and other autoimmune rheumatic diseases. Several advanced non-invasive tools are available for monitoring the microcirculation, including nailfold videocapillaroscopy, which is the best-studied and most commonly used method for distinguishing and quantifying microvascular morphological alterations in SSc. Nailfold videocapillaroscopy can also be used alongside laser Doppler techniques to assist in the early diagnosis and follow-up of patients with dermatomyositis or mixed connective tissue disease. Power Doppler ultrasonography, which has been used for many years to evaluate the vascularity of synovial tissue in rheumatoid arthritis, is another promising tool for the analysis of skin and nailbed capillary perfusion in other autoimmune rheumatic diseases. Other emerging methods include raster-scanning optoacoustic mesoscopy, which offers non-invasive high-resolution 3D visualization of capillaries and has been tested in psoriatic arthritis and SSc. The principle functions and operative characteristics of several non-invasive tools for analysing microvascular changes are outlined in this Review, and the clinical roles of validated or tested imaging methods are discussed for autoimmune rheumatic diseases.

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Targeting interferon-? in hyperinflammation: opportunities and challenges

Fabrizio De Benedetti, Giusi Prencipe, Claudia Bracaglia, Emiliano Marasco & Alexei A. Grom

doi : 10.1038/s41584-021-00694-z

Nature Reviews Rheumatology volume 17, pages678–691 (2021)

Interferon-? (IFN?) is a pleiotropic cytokine with multiple effects on the inflammatory response and on innate and adaptive immunity. Overproduction of IFN? underlies several, potentially fatal, hyperinflammatory or immune-mediated diseases. Several data from animal models and/or from translational research in patients point to a role of IFN? in hyperinflammatory diseases, such as primary haemophagocytic lymphohistiocytosis, various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome, and cytokine release syndrome, all of which are often managed by rheumatologists or in consultation with rheumatologists. Given the effects of IFN? on B cells and T follicular helper cells, a role for IFN? in systemic lupus erythematosus pathogenesis is emerging. To improve our understanding of the role of IFN? in human disease, IFN?-related biomarkers that are relevant for the management of hyperinflammatory diseases are progressively being identified and studied, especially because circulating levels of IFN? do not always reflect its overproduction in tissue. These biomarkers include STAT1 (specifically the phosphorylated form), neopterin and the chemokine CXCL9. IFN?-neutralizing agents have shown efficacy in the treatment of primary haemophagocytic lymphohistiocytosis in clinical trials and initial promising results have been obtained in various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome. In clinical practice, there is a growing body of evidence supporting the usefulness of circulating CXCL9 levels as a biomarker reflecting IFN? production.

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The non-coding RNA interactome in joint health and disease

Shabana A. Ali, Mandy J. Peffers, Michelle J. Ormseth, Igor Jurisica & Mohit Kapoor

doi : 10.1038/s41584-021-00687-y

Nature Reviews Rheumatology volume 17, pages692–705 (2021)

Non-coding RNAs have distinct regulatory roles in the pathogenesis of joint diseases including osteoarthritis (OA) and rheumatoid arthritis (RA). As the amount of high-throughput profiling studies and mechanistic investigations of microRNAs, long non-coding RNAs and circular RNAs in joint tissues and biofluids has increased, data have emerged that suggest complex interactions among non-coding RNAs that are often overlooked as critical regulators of gene expression. Identifying these non-coding RNAs and their interactions is useful for understanding both joint health and disease. Non-coding RNAs regulate signalling pathways and biological processes that are important for normal joint development but, when dysregulated, can contribute to disease. The specific expression profiles of non-coding RNAs in various disease states support their roles as promising candidate biomarkers, mediators of pathogenic mechanisms and potential therapeutic targets. This Review synthesizes literature published in the past 2 years on the role of non-coding RNAs in OA and RA with a focus on inflammation, cell death, cell proliferation and extracellular matrix dysregulation. Research to date makes it apparent that ‘non-coding’ does not mean ‘non-essential’ and that non-coding RNAs are important parts of a complex interactome that underlies OA and RA.

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