15th Anniversary

Hydroxychloroquine and chloroquine are antimalarial drugs commonly used for the treatment of rheumatic diseases. Multiple mechanisms might explain the efficacy and adverse effects of these drugs, but further investigation could lead to the development of more specific and potent drugs.

The ability to resolve, rather than suppress, inflammation could enable new possibilities for the treatment of chronic diseases such as rheumatoid arthritis. Knowing more about the function of immune-regulatory cytokines is the first step towards realizing their therapeutic potential.

In this Review, the authors discuss the emerging evidence of the aetiology of Behçet's. They argue that geographical variation in prevalence, variation in disease expression and evidence of clinical subsets supports the notion that Behçet's is a syndrome rather than a disease.

Janus kinase (JAK) inhibitors are emerging therapeutic agents for the treatment of rheumatic inflammatory diseases. In this Review, the author outlines the safety profile of JAK inhibitors, discussing the potential adverse effects associated with these drugs, such as malignancy, infections and reactivation of herpes zoster.

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.

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.

Intervertebral disc (IVD) degeneration is a common cause of back, neck, and radicular pain. High levels of a number of inflammatory cytokines that are secreted by IVD cells characterize, and are involved in the pathogenesis of, IVD degeneration. In this comprehensive Review, the authors describe the key inflammatory cytokines that are involved in different phases of disc degeneration, and they describe the outcomes of the clinical studies that have investigated blocking cytokine function.

Fibroblast-like synoviocytes (FLS) are cellular effectors of the inflammatory milieu that characterizes and precedes joint destruction in rheumatoid arthritis (RA). But what role do these cells have in creating the same environment to which they respond? Bottini and Firestein delve into the double life of FLS in RA pathogenesis.

The interplay between the cells that regulate bone architecture and the immune system is increasingly recognized. In this Review, as well as providing an overview of fracture treatment and healing, the authors discuss our current knowledge of the part played by inflammation in the fracture repair process. The influence of biomechanical and biological factors on bone healing is also considered, focusing on the effects of excessive local and systemic inflammation, as occurs in autoimmune diseases such as rheumatoid arthritis.

The etiology and pathogenesis of osteoarthritis (OA) are poorly understood, although proinflammatory cytokines are known to be critically implicated in the disease. In this Review, the authors discuss the current knowledge regarding the role of proinflammatory cytokines, particularly interleukin (IL) 1β, tumor necrosis factor and IL 6 in the pathophysiology of OA, and give an overview of efforts to develop adequate and specific anticytokine therapies.

Moving beyond the view of osteoarthritis as a disease of the cartilage, evidence is emerging that synovial inflammation is an important factor in the pathophysiology of the disease. In this article, Sellam and Berenbaum review that evidence, present various methods of assessing synovitis, and discuss the possibility of synovitis-targeted therapy for the treatment of osteoarthritis.

The signaling pathways regulating the closely linked processes of adipogenesis and osteoblastogenesis are controlled by numerous transcription factors. This article focuses on the role of peroxisome proliferator activated receptor γ in the promotion of adipogenesis, and the Wnt–β-catenin and noncanonical Wnt signaling pathways in the promotion of osteoblastogenesis, and the crosstalk between these pathways.

The vitamin D system has both pathophysiological and therapeutic importance for autoimmune disease. In this Review, the authors discuss the role of the vitamin D system in autoimmunity, the mechanistic basis for this role, and present the potential of vitamin D receptor agonists to treat or prevent autoimmune diseases.

White adipose tissue-derived adipokines are closely associated with obesity-related exogenous factors, such as nutrition and lifestyle, and the molecular events that lead to metabolic syndrome, inflammatory and/or autoimmune conditions, and rheumatic diseases. In this Review, Dr Gualillo and colleagues discuss the progress in adipokine research, focussing on the roles of leptin, adiponectin, resistin, visfatin, and other recently identified adipokines.

Osteoporosis results from decreased osteoblast function, increased osteoclast function and increased adiposity of the bone marrow with age. Regulation of the balance between fat and bone in the bone marrow is complex and involves genetic, hormonal and environmental influences. Here, Clifford Rosen outlines a hypothesis that skeletal fragility has its pathogenic roots in pleuripotent marrow stromal cells and their fate as either fat or bone cells.

Molecular biology techniques have enabled the pathophysiologic pathways involved in joint destruction in rheumatoid arthritis to be elucidated at the cellular and molecular level. In this review, the authors discuss the various cell-to-cell and cell-to-matrix interactions, highlighting the role of cytokine-independent pathways and the innate immune system in these processes.

Gender disparities persist in many aspects of working life for women in academic rheumatology. To move forward, we must find ways to address the gender gap in rheumatology with the goal of creating a workforce as diverse as the patient population it serves.

The global COVID-19 pandemic has the potential to severely affect those with rheumatic diseases or who are taking immunosuppressive therapies. Information is lacking as to how these groups will fare if they become infected. A global alliance has rapidly formed to try to address this information deficit.

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.

A new single cell detection technology allows simultaneous measurement of up to 100 surface markers and signaling proteins of immune cells. This method provides the opportunity to make great advances into the scientific understanding of rheumatic disease and the provision of individualized patient care.

Seemingly contrasting genetic backgrounds in anti-citrullinated-protein antibody (ACPA)-positive and ACPA-negative rheumatoid arthritis (RA) support the notion that these are in fact two distinct disease subsets, with different underlying pathogenesis, that might need tailored treatment strategies.

Methotrexate is a proven and efficacious therapy for inflammatory diseases such as rheumatoid arthritis. The main mechanism of action of methotrexate as an anti-cancer drug, at high doses, involves folate antagonism, but what other mechanisms might be operative in the use of this drug at lower doses as an effective anti-inflammatory agent?