Review Articles in 2015

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.

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.

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.

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.

The immunomodulatory properties of vitamin D suggest it plays a central part in inflammatory diseases such as rheumatoid arthritis, a link that has been reinforced by findings from epidemiological andin vitro studies. In this Review, Jeffery et al. provide an overview of the known effects of vitamin D in the immune system and discuss how manipulation of the vitamin D pathway might be used for therapeutic purposes.

Several genetic associations have been identified in patients with spondyloarthropathies, particularly ankylosing spondylitis (AS). The most recent associations uncovered which involve genes in the IL-17/IL-23 pathway enabled a better understanding of the aetiology of spondyloarthropathies, and informed the use of previously existing drugs to treat patients with these diseases—an example of how translation of hypothesis-free medical research can yield new therapeutic strategies.

Osteoarthritis (OA) is a chronic condition that is associated with pain and disability. In this Review, Roos and Arden consider the strategies that are available for modification of risk factors contributing to the development of knee OA. Interventions for prevention and early care of knee OA could help to avoid joint-replacement surgery.

Although a generally safe and effective drug that is widely used in the treatment of gout, allopurinol can in rare instances be associated with severe adverse events. The presentation, risk factors and mechanisms of allopurinol-induced hypersensitivity are the focus of this Review, as well as strategies to avoid or minimize such reactions.

Gout is caused by the precipitation of monosodium urate monohydrate (MSU) crystals in the joints and in other tissues. Although direct observations of MSU crystals as they form on tissues are lacking, morphological findings and comparison with the physiological process of biomineralization suggests possible mechanisms of pathological MSU crystal formation and the conditions that might favour the nucleation and growth of crystals at particular anatomical sites.

Most core sets of outcomes in rheumatology include some patient-reported outcomes (PROs), most commonly pain, function, and patient global assessment of disease activity. According to van Tuyl and Boers, further research is needed to understand the value of the patient assessment and to define how these three key PROs contribute to the broader concept of health-related quality of life.

The burden of cardiovascular disease is high in patients with inflammatory joint disease, owing to the presence of inflammation and traditional cardiovascular risk factors. Current management of cardiovascular risk factors and control of disease activity are unsatisfactory, and patients could benefit from improvements in screening and coordination between the cardiology and rheumatology branches of health care.

The increasing use of biosimilars in the context of rheumatic diseases has been met with several challenges unique to this type of drugs. In this Review, Dörner and Kay describe the fast adoption of biosimilar agents worldwide, highlighting the different approaches to regulation implemented by national and supranational health care policy-makers. Issues such as extrapolation of indications and the definition of strategies for adequate postmarketing pharmacovigilance are also discussed.

Inflammation can be initiated by exogenous pathogen-associated molecular patterns (PAMPs) or by endogenous damage-associated molecular patters (DAMPs), but the contribution of each activation mechanism to reduction–oxidation (redox) stress and, ultimately, to the immunopathogenesis of autoinflammatory diseases remains elusive. In this Review, Varga and colleagues discuss how improved knowledge of mechanisms of inflammation initiation and propagation might help identify new therapeutic targets for patients with autoinflammatory diseases.