Reviews & Analysis

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the central nervous system that is associated with several immunosuppressive therapies. In this Opinion article, Calabrese and colleagues propose a ranking of immunosuppressive agents based on their risk of PML to support a better-informed decision-making process.

A group of experts in rheumatology and dermatology has identified many unmet needs in the care of patients with psoriatic arthritis and offered potential solutions. But do their recommendations go far enough?

The strongest evidence yet that hypertrophic chondrocytes can turn into osteoblasts could affect not only our understanding of skeletal development, but also the use of research tools thought to be cartilage-specific.

Pulmonary complications are an important extra-articular manifestation of connective tissue disease (CTD) and a major cause of mortality. Here, the authors provide a broad overview of interstitial lung disease in the context of CTD, providing insights into pathogenesis, classification and management of the disease.

In osteoarthritis (OA), chronic, low-grade inflammatory processes promote the symptoms and progression of the disease. In this Review, the authors discuss the inflammatory pathophysiology in OA, including networks of inflammatory mediators in OA joints, transcriptional reprogramming of chondrocytes, and abnormal bioenergetics and proteostasis mechanisms, and consider the potential to target these processes for the treatment of OA.

In this Review, skeletal ontogeny is compared to fracture healing mechanisms. The authors describe developments in our understanding of the different stages of fracture healing as well as the latest therapies tested in animal models and in clinical trials, focusing on bone morphogenetic proteins or parathyroid hormone based treatments.

Although osteoarthritis can be slowed by biologic therapy, surgical interventions are necessary to recover cartilage function. In this Review of cartilage repair techniques, the authors outline how currently accepted methods can fall short in providing a long-term solution of hyaline cartilage regeneration and discuss preclinical and clinical trials of new cell scaffold-based, cell-free scaffold-based and scaffold-free procedures.

In this Review, Martinon and Aksentijevich highlight the latest developments in research into the pathogenesis of autoinflammatory diseases. Newly discovered disease-causing mutations and molecular pathways underlying inherited autoinflammatory diseases are discussed.

Patients with rheumatoid arthritis who are hemiplegic, and also mice with denervated hindpaws and experimentally-induced arthritis, can develop unilateral arthritis. But is a specific branch of the nervous system involved in this asymmetry, or does a lack of innervation alter the microvasculature and promote vascular impermeability?

Macrophage activation syndrome (MAS) in systemic juvenile idiopathic arthritis (sJIA) is difficult to distinguish from active sJIA or sepsis. A collaborative effort scoring the performance of different clinical diagnostic criteria provides valuable guidance to clinicians, but challenges in the diagnosis of sJIA-related MAS remain.

A lack of universally accepted classification criteria for patients with juvenile spondyloarthritis (SpA) has hindered efforts to develop tools to assess the severity and progression of this disease. With the publication of a new juvenile SpA disease activity index, has this gap now been bridged, and is it a comprehensive tool for the clinic?

Given the known involvement of IL-36 in psoriasis it might be surprising that the latest mouse models show that inhibiting IL-36 signalling does not alter the course of inflammatory arthritis. Can we now add IL-36 to the list of inflammatory mediators that are not viable DMARD targets?

Diagnostic imaging in rheumatology has become an important feature of the management of a variety of rheumatic diseases. This Timeline Perspectives charts the progress in the field of imaging in rheumatology over the past few decades, with particular emphasis on developments in radiography, MRI and ultrasonography.

Sex steroid hormones are likely to influence risk and expression of autoimmune diseases through modulation of key immune pathways. In this Review, Hughes and Choubey discuss the immunomodulatory mechanisms behind the sexual dimorphism observed in patients with systemic lupus erythematosus and rheumatoid arthritis, and focus on how oestrogen and progesterone affect manifestation of these diseases.

A screening program for hyperuricaemia and gout would aim to identify those individuals with elevated serum urate and thus enable intervention to prevent the onset of gout. However, the data supporting a role for screening in this setting is far from complete. Stamp and Dalbeth outline the important issues around a screening programme for hyperuricaemia and gout, and highlight areas where further research is required before such a programme could be considered.

Elevated serum uric acid levels and gout are linked with the development of several comorbid conditions including hypertension, metabolic syndrome, chronic kidney disease and cardiovascular disease. In this Review, the authors explore the mechanisms underlying these associations and discuss the potential of appropriate treatment strategies to improve cardiovascular and renal outcomes in patients with hyperuricaemia and gout.

Systemic sclerosis (SSc) is a complex autoimmune disease. Here, the authors describe the current understanding of the genetics of SSc and how genetic risk factors can influence disease pathogenesis. Available evidence of the role of epigenetic factors (including microRNAs and DNA methylation patterns) in disease development is also discussed.

Although paraneoplastic syndromes are rare, it is important that rheumatologists can recognise the typical clinical patterns of these syndromes in their rheumatic disease patients to allow for timely diagnosis and potentially life-saving therapy. Here, the authors focus on well-defined paraneoplastic musculoskeletal syndromes for which the evidence of a causal relationship to an underlying tumour is not only based on a temporal relationship but also on underlying pathomechanisms.

IL-6 has been linked to numerous inflammatory conditions (such as rheumatoid arthritis), and many IL-6-directed therapies are currently in development. The authors outline the basic biology of IL-6 and IL-6 signalling pathways before discussing the clinical implications of targeting IL-6 in the context of rheumatic diseases. Current and future indications for the use of IL-6-targeted therapies and safety of these agents are discussed.

Transforming growth factor-β (TGF-β), a key component in altered vascular and connective tissue homeostasis, is often linked with the pathogenesis of fibrotic diseases such as systemic sclerosis (SSc). In this Review, Lafyatis highlights the known mechanisms ofin situTGF-β activation and summarizes the evidence that place TGF-β at the centre of SSc pathogenesis.