Reviews & Analysis

Since glucocorticoids were first used to treat patients with rheumatoid arthritis in 1949, they have become the most common therapy for inflammatory disorders; however, their use is associated with major metabolic adverse events. Here, we review three 2015 reports with clinical and fundamental implications for the use of glucocorticoid therapy in rheumatology.

Several microRNAs (miRNAs) that are involved in the regulation of cellular metabolism or immune processes are deregulated in patients with rheumatic diseases, such as rheumatoid arthritis or osteoarthritis. These small inhibitory molecules offer considerable potential for the treatment of these disorders, but a multidisciplinary approach is needed to limit their potential adverse effects through, for example, improved specificity and delivery.

The mechanistic target of rapamycin (mTOR) pathway has a central role in cell activation, particularly in cells of the immune system. Discovery of the involvement of mTOR in the pathophysiology of several human disorders has led to the development of inhibitors and upstream regulators of this pathway to treat autoimmune and hyperproliferative pathologies — hallmarks of rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus.

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.

Despite the clinical success of therapeutics that inhibit TNF, gaps remain about the biology of this pleiotropic cytokine. This Review explores the latest discoveries related to TNF signalling pathways, TNF-induced gene expression, and the homeostatic and pathogenic functions of TNF, as well as the implications of these findings for therapeutics for TNF-mediated diseases.

Lipopolysaccharide derived from gastrointestinal microbiota contributes to systemic inflammation and obesity. Huang and Kraus propose that lipopolysaccharide is a major risk factor for osteoarthritis (OA), and suggest that therapeutic strategies for the reduction of systemic levels of lipopolysaccharide should be considered for prevention and treatment of OA.

Members of the IL-1 family of cytokines have been implicated in several autoimmune diseases, including rare hereditary syndromes and more frequent diseases such as gout. Once processed and activated, IL-1α and IL-1β promote inflammation, monocyte and neutrophil infiltration and, ultimately, tissue damage and stress. Therapies that target IL-1 have already shown clinical efficacy, and are enabling a better understanding of the biology of this cytokine family.

Polymyalgia rheumatica (PMR) is an inflammatory disorder of unknown aetiology that can be extremely disabling when active. Glucocorticoids are currently the therapy of choice for patients with PMR, but responsiveness to treatment varies considerably. The identification of different morphological patterns of disease defined by distinct extracapsular or capsular-based inflammation might, at least in part, explain this variability in responses to treatment.

Granulocyte-macrophage colony stimulating factor (GM-CSF) is a cytokine with a wide range of biological effects that span innate and adaptive immunity processes. As our knowledge of the biology of GM-CSF improves, its potential as a therapeutic target in rheumatic diseases is being acknowledged, and the first early phase clinical trials of GM-CSF inhibition in patients with inflammatory disorders have produced encouraging results.

Cytokines that signal via the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway have diverse roles in normal immune responses as well as immune-mediated diseases. This Review provides an overview of these roles as well as the JAK–STAT pathway, and discusses emerging therapies that block JAKs and the cytokines that signal through them.

Proangiogenic signalling pathways are activated in chronic inflammation, but although antiangiogenic treatments are routinely incorporated into cancer therapy, surprisingly few clinical trials have investigated this approach in patients with chronic inflammatory diseases. However, this situation could soon change — a wide range of small-molecule inhibitors with improved specificity, and techniques to target such inhibitors to specific cell types, are currently undergoing clinical and preclinical development.

Chemokines and their receptors are involved in the pathogenesis of rheumatoid arthritis. Therapeutic strategies targeting chemokine pathways have had promising results in animal models, but have been less successful in human trials. Szekanecz and Koch discuss the different approaches to chemokine-pathway targeting and the possible reasons for the difficulty in developing effective therapies.

The bone marrow niche is a unique microenvironment that integrates the physiology of the skeleton and the marrow to maintain the haematopoietic stem cell pool and support whole-organism homeostasis. Reagan and Rosen examine the features of this microenvironment and the consequences of its disruption, particularly in relation to invasion by cancer cells, and discuss how better understanding of the niche could inform treatments for various disorders including skeletal diseases and malignancies.

Anti-DNA antibodies are serological hallmarks of systemic lupus erythematosus, but many questions remain unanswered regarding their origins and pathological properties, as well as the relative merits of different assay formats. Understanding the mechanisms of DNA binding and pathogenesis relating to anti-DNA antibodies can aid the development of diagnostic and theranostic assays.

Nephritis remains an important cause of morbidity and mortality in many patients with systemic lupus erythematosus (SLE), but knowledge of the factors contributing to the heterogeneity of kidney disease in these patients has been lacking. This article outlines various pathogenic pathways that contribute to renal damage in SLE and explains how disease phenotyping based on these mechanisms could lead to the novel and individualized therapies for patients with lupus nephritis.

A new study attributes the pathogenicity of anti-Ro60 autoantibodies and type I interferon in systemic lupus erythematosus and Sjögren syndrome to Alu retroelements, but is this RNA the complete story?

This article presents the concept that Behçet disease and several spondyloarthropathies might have a common immunopathogenetic basis. The authors propose that barrier dysfunction in environmentally exposed organs, and aberrant innate immune reactions at sites of mechanical stress, trigger secondary adaptive immune CD8⁺T-cell responses characterized by prominent neutrophilic inflammation. The differential immunopathology of these 'MHC-I-opathies' could reflect antigenic differences in target tissues.

Glucocorticoids are the mainstay of treatment for patients with polymyalgia rheumatica (PMR) and often produce substantial clinical improvements, but treatment can be complicated by relapse, adverse effects of therapies, and concomitant conditions. New recommendations aim to guide clinicians and improve the management of this disorder.

Functional MRI (fMRI) is increasingly used in efforts to unravel the neuropathological processes of neuropsychiatric systemic lupus erythematosus (NPSLE). Standardization of scan protocols, imaging expertise and disease-related confounders of neuronal activities remain major challenges to the use of fMRI in the diagnosis and prognosis of NPSLE.

In the past 10 years, the rheumatology community has seen an explosion in the number of new therapies licensed for use across the rheumatic diseases, many with outstanding clinical success. Here, the drugs and strategies that constitute landmarks in the management of rheumatic diseases are highlighted.