Nature Reviews Rheumatology

Most rheumatic and musculoskeletal diseases (RMDs) can be placed along a spectrum of disorders, with autoinflammatory diseases (including monogenic systemic autoinflammatory diseases) and autoimmune diseases (such as systemic lupus erythematosus and antiphospholipid syndrome) representing the two ends of this spectrum. However, although most autoinflammatory diseases are characterized by the activation of innate immunity and inflammasomes and classical autoimmunity typically involves adaptive immune responses, there is some overlap in the features of autoimmunity and autoinflammation in RMDs. Indeed, some ‘mixed-pattern’ diseases such as spondyloarthritis and some forms of rheumatoid arthritis can also be delineated. A better understanding of the pathogenic pathways of autoinflammation and autoimmunity in RMDs, as well as the preferential cytokine patterns observed in these diseases, could help us to design targeted treatment strategies.

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Advances in epigenetics in systemic sclerosis: molecular mechanisms and therapeutic potential

Pei-Suen Tsou, John Varga & Steven O’Reilly

doi : 10.1038/s41584-021-00683-2

Nature Reviews Rheumatology volume 17, pages596–607 (2021)

Systemic sclerosis (SSc) is a prototypical inflammatory fibrotic disease involving inflammation, vascular abnormalities and fibrosis that primarily affect the skin and lungs. The aetiology of SSc is unknown and its pathogenesis is only partially understood. Of all the rheumatic diseases, SSc carries the highest all-cause mortality rate and represents an unmet medical need. A growing body of evidence implicates epigenetic aberrations in this intractable disease, including specific modifications affecting the three main cell types involved in SSc pathogenesis: immune cells, endothelial cells and fibroblasts. In this Review, we discuss the latest insights into the role of DNA methylation, histone modifications and non-coding RNAs in SSc and how these epigenetic alterations affect disease features. In particular, histone modifications have a role in the regulation of gene expression pertinent to activation of fibroblasts to myofibroblasts, governing their fate. DNA methyltransferases are crucial in disease pathogenesis by mediating methylation of DNA in specific promoters, regulating expression of specific pathways. We discuss targeting of these enzymes for therapeutic gain. Innovative epigenetic therapy could be targeted to treat the disease in a precision epigenetics approach.

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The endothelium–bone axis in development, homeostasis and bone and joint disease

Jan Tuckermann & Ralf H. Adams

doi : 10.1038/s41584-021-00682-3

Nature Reviews Rheumatology volume 17, pages608–620 (2021)

Blood vessels form a versatile transport network that is best known for its critical roles in processes such as tissue oxygenation, metabolism and immune surveillance. The vasculature also provides local, often organ-specific, molecular signals that control the behaviour of other cell types in their vicinity during development, homeostasis and regeneration, and also in disease processes. In the skeletal system, the local vasculature is actively involved in both bone formation and resorption. In addition, blood vessels participate in inflammatory processes and contribute to the pathogenesis of diseases that affect the joints, such as rheumatoid arthritis and osteoarthritis. This Review summarizes the current understanding of the architecture, angiogenic growth and functional properties of the bone vasculature. The effects of ageing and pathological conditions, including arthritis and osteoporosis, are also discussed.

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Early-stage symptomatic osteoarthritis of the knee — time for action

Armaghan Mahmoudian, L. Stefan Lohmander, Ali Mobasheri, Martin Englund & Frank P. Luyten

doi : 10.1038/s41584-021-00673-4

Nature Reviews Rheumatology volume 17, pages621–632 (2021)

Osteoarthritis (OA) remains the most challenging arthritic disorder, with a high burden of disease and no available disease-modifying treatments. Symptomatic early-stage OA of the knee (the focus of this Review) urgently needs to be identified and defined, as efficient early-stage case finding and diagnosis in primary care would enable health-care providers to proactively and substantially reduce the burden of disease through proper management including structured education, exercise and weight management (when needed) and addressing lifestyle-related risk factors for disease progression. Efforts to define patient populations with symptomatic early-stage knee OA on the basis of validated classification criteria are ongoing. Such criteria, as well as the identification of molecular and imaging biomarkers of disease risk and/or progression, would enable well-designed clinical studies, facilitate interventional trials, and aid the discovery and validation of cellular and molecular targets for novel therapies. Treatment strategies, relevant outcomes and ethical issues also need to be considered in the context of the cost-effective management of symptomatic early-stage knee OA. To move forwards, a multidisciplinary and sustained international effort involving all major stakeholders is required.

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Management of gout in chronic kidney disease: a G-CAN Consensus Statement on the research priorities

Lisa K. Stamp, Hamish Farquhar, Huai Leng Pisaniello, Ana B. Vargas-Santos, Mark Fisher, David B. Mount, Hyon K. Choi, Robert Terkeltaub, Catherine L. Hill & Angelo L. Gaffo

doi : 10.1038/s41584-021-00657-4

Nature Reviews Rheumatology volume 17, pages633–641 (2021)

Gout and chronic kidney disease (CKD) frequently coexist, but quality evidence to guide gout management in people with CKD is lacking. Use of urate-lowering therapy (ULT) in the context of advanced CKD varies greatly, and professional bodies have issued conflicting recommendations regarding the treatment of gout in people with concomitant CKD. As a result, confusion exists among medical professionals about the appropriate management of people with gout and CKD. This Consensus Statement from the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) discusses the evidence and/or lack thereof for the management of gout in people with CKD and identifies key areas for research to address the challenges faced in the management of gout and CKD. These discussions, which address areas for research both in general as well as related to specific medications used to treat gout flares or as ULT, are supported by separately published G-CAN systematic literature reviews. This Consensus Statement is not intended as a guideline for the management of gout in CKD; rather, it analyses the available literature on the safety and efficacy of drugs used in gout management to identify important gaps in knowledge and associated areas for research.

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Publisher Correction: Global epidemiology of systemic lupus erythematosus

Megan R. W. Barber, Cristina Drenkard, Titilola Falasinnu, Alberta Hoi, Anselm Mak, Nien Yee Kow, Elisabet Svenungsson, Jonna Peterson, Ann E. Clarke & Rosalind Ramsey-Goldman

doi : 10.1038/s41584-021-00690-3

Nature Reviews Rheumatology volume 17, page642 (2021)

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