Review Articles in 2016

How and why systemic autoimmunity targets the joints in rheumatoid arthritis remains a major unanswered question. In this Review, Catrina et al. discuss the evidence for a driving role for osteoclasts in the homing of autoimmunity to the joints.

The endoplasmic reticulum (ER) is vital for cellular function and differentiation in every organ system. In this Review, the authors discuss how cells respond to ER stress and outline the ways that this stress can contribute towards rheumatic diseases.

In this Review, the authors discuss the use of mass spectrometry imaging in rheumatology. This technique enables the identification and spatial localization of molecules in tissues, with potential applications in both clinical and research settings.

In this Review, Tsokos et al. describe recent advances in our understanding of systemic lupus erythematosus (SLE) that are driving repurposing of existing drugs as well as development of new treatments. Cytokines, tolerance pathways, local tissue mediators, and epigenetic mechanisms all show promise as novel targeted therapies that could lead to individualized care in SLE.

Cronstein and Sitkovsky discuss the metabolic changes that regulate adenosine levels in inflamed tissue, the receptors that mediate the effects of adenosine and their role in rheumatic diseases, as well as the potential role for therapeutic targeting of adenosine and its receptors.

Genetic association studies have uncovered more than 100 genetic loci related to susceptibility to rheumatoid arthritis. This Review discusses the latest insights into rheumatoid arthritis pathogenesis gained from genetic studies and their application for drug discovery and development.

Methotrexate remains the first-line therapy for rheumatoid arthritis (RA). However, not all treated patients respond, and its mechanism of action remains incompletely understood. This Review describes putative mechanisms of action of methotrexate at the low doses used in RA and discusses potential biomarkers of treatment response, which could ultimately inform precision use of this therapy.

Reverse translation of data obtained from trials of B-cell-targeted therapies in systemic lupus erythematosus (SLE), along with advances in understanding of B-cell intracellular signalling pathways and post-activation status, highlight pathogenic roles for autoantigen-presenting B cells and regulatory B cells in autoimmune diseases. These insights could lead to innovative treatments for SLE based on modulation of B-cell activation and regulatory functions.

Alarmins are endogenous molecules that have host-protective roles but have also been implicated in the pathogenesis of joint diseases. This Review summarizes the roles of alarmins in osteoarthritis and inflammatory arthritis, highlighting them as novel therapeutic targets in these diseases.

In this Review, the authors summarize the changes that occur in the biocomposite formed by articular cartilage and bone during the evolution of osteoarthritis (OA). They also discuss how an improved understanding of these changes could be exploited to develop new therapies for patients with OA.

Dendritic cells are key regulators of both immunity and tolerance, and display a remarkable functional heterogeneity. In this Review, the authors discuss how the function and distribution of different dendritic cell subsets change in autoimmune diseases.

Several lymphocyte subsets have innate-like characteristics. In this Review, the authors summarize the roles of these innate lymphocytes in autoimmunity, emphasizing that further improvements in our understanding could identify novel therapeutic targets for autoimmune diseases.

Understanding the global burden of SLE, and the factors that contribute to the considerable variation in its worldwide incidence and prevalence (particularly health disparities, costs, and socioeconomic status), is expected to inform future efforts to improve patient outcomes while optimizing resource allocation and decreasing associated health-care costs.

In this article, Cuda et al. discuss the role of programmed cell death mechanisms in the pathogenesis of rheumatic diseases, and provide an overview of the experimental data showing the function of the apoptotic machinery of phagocytes in the development of tissue inflammation.

Emerging evidence indicates that the inflammatory mechanisms involved in the pathophysiology of osteoarthritis (OA) differ from those in rheumatoid arthritis. This Review explores the mechanisms of chronic, low-grade inflammation in OA, discusses the evidence of their central role in its pathogenesis, and explores how they might be targeted to prevent or treat OA.

Cancer can be successfully treated by blocking inhibitory immune checkpoint receptors, but in some patients these treatments cause immune-related adverse effects that can resemble autoimmune responses. This Review discusses what rheumatologists can learn from these observations and summarizes progress in therapeutically targeting inhibitory receptors in autoimmune diseases.

The type of anti-neutrophil cytoplasmic antibody (ANCA) seems to be a major determinant of clinical presentation in ANCA-associated vasculitides (AAV). The authors of this Review argue that ANCA specificity for PR3 or MPO provides clinically useful information and should be used in the classification of AAV.

This Review discusses the current treatment of the manifestations of primary Sjögren syndrome and summarizes ongoing clinical trials. The authors examine the status of biologic therapies, the challenges relating to clinical trial design and potential targets for the future therapies.

Mendelian randomization analysis makes use of random inheritance of genetic variants to limit confounding in tests for causal relationships between risk factors and disease outcomes. This Review considers the current and future applications, as well as the limitations, of Mendelian randomization in rheumatology.

Mental health-related comorbidities can negatively affect the quality of life of patients with rheumatoid arthritis. In this Review, the authors discuss how psychological manifestations interact with disease processes, new insights into neurological processing in chronic pain, and psychological interventions.