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Iain McInnes discusses a 1994 paper by Ravinder Maini, Marc Feldmann and colleagues that showed a specific cytokine (tumour necrosis factor) could be targeted for therapeutic benefit in patients with rheumatoid arthritis.

In the double-blind, placebo-controlled phase 2 ARGO trial, patients with active psoriatic arthritis treated with a nanobody targeting IL-17A and IL-17F showed substantially better disease response rates compared with those receiving placebo treatment.

Serological analysis and infection outcomes of participants in the multi-center, prospectively enrolled OCTAVE cohort, comprising 2,686 participants with immune-suppressive diseases who recieved two COVID-19 vaccines, reveals specific clinical phenotypes that might benefit from specific COVID-19 therapeutic strategies.

The contributions of key cytokines in rheumatoid arthritis (RA) pathogenesis, including TNF, IL-1, JAK-dependent cytokines, GM-CSF and chemokines, can be considered not only individually, but also in the context of an overall 'RA tissue response'. In this Opinion article, the authors provide an overview of the roles of cytokines in the innate, adaptive and stromal immune responses, and discuss how systematic analysis of cytokine pathways could yield new insights into disease pathogenesis and facilitate stratification for therapy.

The enthesis is the region at the junction between tendon and bone and has been suggested to be a key target in spondyloarthritic diseases. This zone is now shown to contain a unique population of resident T cells, which, when activated by the cytokine interleukin-23 (IL-23), can promote pathogenesis that is characteristic of spondyloarthritis (pages 1069–1076).

In this Perspective, McInnes and Gravallese highlight the remarkable progress made over the past 20 years in treating immune-mediated inflammatory diseases. The available therapies have progressed from broad-spectrum immune modulators to highly targeted biological and small-molecule agents as our understanding of disease mechanisms has advanced.

Axl is a TAM receptor that can inhibit Toll-like receptor (TLR) -induced pro-inflammatory production by dendritic cells (DC). Here the authors show that miR-34a targets Axl to control CD1c+ DC activity in mice, and that miR-34a-deficient mice are resistant to collagen-induced arthritis, whereas DCs from patients with rheumatoid arthritis have high levels of miR- 34a.

Collagen 3 is increased during tendon repair, but is then replaced by Collagen 1 that has superior biomechanical properties. Here the authors show that IL-33 is induced by tendon damage and regulates miR-29a, which controls Collagen 3 production and feeds back on IL-33, orchestrating tendon repair.

Cytokine targeting is an established approach for treating patients with rheumatoid arthritis following success with tumor-necrosis-factor and interleukin-1 blockade. Many patients fail to respond completely to these cytokine antagonists, however, meaning that novel cytokine targets are keenly sought. This review describes the new generation of anticytokine therapies that are in preclinical and clinical development.

Pathways associated with inflammation are thought to account for increased vascular risk in patients with chronic inflammatory diseases. This Review summarizes key epidemiologic, physiologic and model data that implicate involvement of tumor necrosis factor, a pivotal cytokine in the inflammatory cascade, in atherosclerosis.

How MICL recognizes and autoregulates the formation of neutrophil extracellular traps is explored in mouse models and human patients where disease severity is associated with aberrant neutrophil extracellular trap formation.

MiR-155 is thought to inhibit PU.1 and thereby drive antigen-induced B-cell maturation. Here the authors show that patients with rheumatoid arthritis have high B-cell miR-155 expression and that an antagomir can rescue PU.1 expression, suggesting potential therapeutic avenues to treat rheumatoid arthritis.

The heterogenous nature of rheumatoid arthritis renders the prediction of responsiveness to biological treatments difficult. Here the authors analyze bulk RNA-seq data from the STRAP trial (n = 208) to build a machine-learning model for predicting responses to etanercept, tocilizumab and rituximab with AUCs around 0.75 to potentially assist in therapy planning.

Despite having increased cardiovascular risk, patients with rheumatoid arthritis (RA) often have low serum cholesterol levels. In this Review, the authors discuss this putative 'lipid paradox', highlighting the relationships of inflammation and anti-inflammatory therapy with lipid profiles in RA.

In a rheumatoid joint, a hierarchical network of cytokines controls immunological processes that promote autoimmunity, chronic inflammation and tissue destruction in rheumatoid arthritis. As proposed in this Review, defining these functional hierarchies may present new opportunities for treating the disease.

Discerning which mediators drive pathogenesis in chronic inflammatory diseases can be complex: immune cells can release various pathogenic cytokines, and numerous cytokines may either cause one specific disease or many. Human validation and mechanistic studies will be necessary to identify the key immune cells and cytokines for a given inflammatory disorder and to pinpoint which cytokine might be the appropriate target for tackling each disease. In 'Bedside to Bench', Georg Schett et al. discuss how human trials targeting different cytokines suggest the existence of a hierarchical framework of cytokines that defines groups of chronic inflamatory diseases rather differently from the homogenous molecular disease pattern previously assumed. In 'Bench to Bedside', Vijay Kuchroo and Dominique Baeten peruse the role of interleukin-17A as drug target in several autoimmune diseases to highlight how success in the clinic will need understanding of pathogenic pathways and the immunological and tissue context of each inflammatory disease.

Multiple subpopulations of synovial tissue macrophages with varied transcriptional, phenotypic and functional features may contribute to disease flare and tissue repair in patients with active rheumatoid arthritis and patients in clinical remission.

Deep clinical phenotyping at 28–60 days post-discharge of patients who had been hospitalized with COVID-19 and subsequent long-term follow-up with electronic health records reveal evidence of persistent cardio-renal involvement.

An inverse relationship between BMI and risk of death has been noted in patients with rheumatoid arthritis. Does being overweight or obese really have a favourable effect on mortality in these individuals, or could other factors explain the association?

It is important to understand the correlates of protection against SARS-CoV-2 and its variants for future vaccine design. Here, the authors show that the complement system enhances the antibody-mediated neutralisation of SARS-CoV-2 via increased inhibition of virus-host interactions.

Several molecular pathways and cellular effector functions have been described for the pathology of rheumatoid arthritis, but fundamental questions remain about the basic organization of disease-driving immune responses. In this Review, Benson and colleagues describe how intact tissue imagingin vivohas facilitated studies of the dynamic nature of cellular immune responses, and how these findings can be translated to new therapeutics.

Advances in our understanding of immune cell receptors and the development of biologic agents targeting them have revolutionized the treatment of rheumatoid arthritis (RA). Now, inhibitors of kinases integral to the signalling pathways downstream of these receptors have been added to the therapeutic armamentarium. This Review discusses the signalling pathways and small-molecule inhibitors of their component kinases that have already shown, or are predicted to show, promise in the treatment of RA.

In this Review, the authors discuss how emerging insights into the tissue-specific pathogenetic mechanisms underlying clinical heterogeneity in psoriatic arthritis support the need for tissue-based precision therapy for the disease.

Neutrophils persist in the joints of individuals with inflammatory arthritis, where they contribute to disease. The molecular basis of this persistence is now shown to hinge on the forkhead transcription factor Foxo3a. Foxo3a suppresses expression of Fas ligand, preventing neutrophil apoptosis (pages 666–671).

In this Review, the authors discuss age-related arthropathy and the similarities and differences between childhood loss of immune tolerance and adult development of immune-mediated arthritis, and develop three hypotheses describing age-related mechanisms that contribute to the onset of arthritis.

The field of rheumatology has seen remarkable progress in the past 70 years. This Perspectives article provides a concise overview of developments in the diagnosis and management of musculoskeletal rheumatic diseases, and what the future of rheumatology might hold.

Advances in synovial tissue research have improved our understanding of inflammatory arthritides, particularly rheumatoid arthritis, and have identified potential biomarkers that could be used for diagnosis, disease stratification, and predicting disease course and treatment response.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

Tendon disorders are common and confer a large socioeconomic burden. This Review discusses the role of inflammatory mechanisms in tendon homeostasis and resolution of tendon damage, which are crucial to consider in developing novel therapeutics for tendinopathies.

There are multiple immune-based therapeutics available for some of the most prevalent autoimmune diseases, but for others, there are few or no approved immune therapies. This dichotomy poses discrete challenges. First, for diseases in which multiple therapy choices exist, a rational decision tree is required to select the best therapy. Second, we must devise new strategies for the autoimmune diseases that have the highest unmet clinical need. This commentary outlines new strategies for designing more efficient and selective approaches for immune therapy of autoimmune diseases.

Breakthroughs in the field of rheumatology have transformed the management of rheumatic diseases and improved patient outcomes, but clinical challenges remain. Looking back at ‘older’ drugs could provide new lessons for future drug strategies and development.

A working group of Academia Europaea proposes the addition of a ‘ring diagram’ in clinical publications for the quick evaluation of translational implications.

The most recently described member of the interleukin-1 (IL-1) family, IL-33, as described in this Review, has an important role in immune regulation, as well as in infectious and inflammatory diseases, and thereby could have therapeutic potential.

Yanick Crow, Sun Hur and colleagues show that gain-of-function mutations in IFIH1 cause a spectrum of neural and immunological phenotypes associated with enhanced interferon signaling. The mutations increase the affinity of IFIH1 for RNA, leading to immune upregulation and inflammatory disease.

Most rheumatic and musculoskeletal diseases (RMDs) fall along a spectrum of disorders from autoinflammatory diseases to autoimmune diseases, with ‘mixed-pattern’ RMDs having features of autoinflammation and autoimmunity. A better understanding of the pathogenic pathways of autoinflammation and autoimmunity in RMDs should enhance targeted treatment strategies.

Rheumatoid diseases such as rheumatoid arthritis are associated with accelerated atherosclerosis, increased cardiovascular morbidity and mortality. The early signs of cardiovascular disease therefore need to be recognized in these patients so that effective cardiovascular protection can be introduced. In this Review the authors discuss validated techniques that are currently available to determine subclinical atherosclerosis in patients with rheumatic conditions.

Rheumatoid arthritis is a chronic, inflammatory, autoimmune disease that primarily affects the joints. This Primer by Smolen et al. provides the latest insights into the epidemiology, genetics, pathophysiology, diagnostic approaches, clinical assessment and management of rheumatoid arthritis.

In this Review, the authors discuss a comprehensive mechanistic concept of psoriatic arthritis, including discussion of the genetic, biomechanical, metabolic and microbial factors that contribute to the development of the disease as well as its manifestations and consequences.

Depression is a common comorbidity in rheumatoid arthritis, and shared immune mechanisms link the two conditions. This Review explores potential peripheral and central interactions between the immune system and brain, the understanding of which could aid in the development of novel therapeutics.