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Journal: Nature reviews. Rheumatology

40

Metabolism is important for cartilage and synovial joint function. Under adverse microenvironmental conditions, mammalian cells undergo a switch in cell metabolism from a resting regulatory state to a highly metabolically activate state to maintain energy homeostasis. This phenomenon also leads to an increase in metabolic intermediates for the biosynthesis of inflammatory and degradative proteins, which in turn activate key transcription factors and inflammatory signalling pathways involved in catabolic processes, and the persistent perpetuation of drivers of pathogenesis. In the past few years, several studies have demonstrated that metabolism has a key role in inflammatory joint diseases. In particular, metabolism is drastically altered in osteoarthritis (OA) and aberrant immunometabolism may be a key feature of many phenotypes of OA. This Review focuses on aberrant metabolism in the pathogenesis of OA, summarizing the current state of knowledge on the role of impaired metabolism in the cells of the osteoarthritic joint. We also highlight areas for future research, such as the potential to target metabolic pathways and mediators therapeutically.

Concepts: Protein, Amino acid, Metabolism, Adenosine triphosphate, Enzyme, Organism, Metabolic pathway, Catabolism

28

Obesity and knee osteoarthritis (OA), two of the most common chronic diseases, are often comorbid. Obesity increases the risk of knee OA by a variety of mechanisms, such as increased joint loading and changes in body composition, with detrimental effects related to metainflammation and behavioural factors, including diminished physical activity and subsequent loss of protective muscle strength. These complex interactions present a challenge to the managing physician. The risk of knee OA related to weight gain and obesity begins from an early age. Weight loss reduces the risk of incident knee OA, and, in established disease, reduces symptoms, improves function and is likely to reduce disease progression. We review strategies to facilitate weight loss, with particular reference to their application in people with knee OA. Although knee OA presents intrinsic barriers to weight management, weight loss is possible at all stages of disease. Exercise or muscle strengthening are desirable for general health and to improve function, but are not essential to achieve weight loss and a successful symptomatic result. The degree of weight loss required to achieve benefit might be greater with increasing disease severity. Finally, we outline the need for a societal approach to tackle obesity-related OA.

Concepts: Medicine, Cancer, Obesity, Muscle, Physical exercise, Osteoarthritis, Adipose tissue, Joint

28

A fundamental change in management of antineutrophil cytoplasmic antibody-associated vasculitis in the past 10 years is the early focussed use of aggressive immunosuppression, using regimens comprised of widely available medications. Using a clinical framework to quantify morbidity, we can induce remission in most patients within 3-6 months using glucocorticoids plus methotrexate, cyclophosphamide or rituximab, with additional plasmapheresis when indicated. Difficulty in maintaining remission probably relates to the difference between true pathophysiological remission and the absence of clinical, serological or radiological evidence of disease activity. For surviving patients, the cumulative problems of relapse, burden of disease, or its treatment are coupled with pre-existing diseases or new conditions arising since diagnosis. Initial early control should reduce subsequent damage, but what effect it will have on relapse is not clear. In the absence of a cure, future trials should focus on reducing toxicity and comorbidity as well as controlling disease.

Concepts: Medicine, Epidemiology, Cancer, Disease, Cure, Chemotherapy, Rheumatoid arthritis, Wegener's granulomatosis

25

Anti-neutrophil cytoplasmic antibodies (ANCAs) are valuable laboratory markers used for the diagnosis of well-defined types of small-vessel vasculitis, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). According to the 1999 international consensus on ANCA testing, indirect immunofluorescence (IIF) should be used to screen for ANCAs, and samples containing ANCAs should then be tested by immunoassays for proteinase 3 (PR3)-ANCAs and myeloperoxidase (MPO)-ANCAs. The distinction between PR3-ANCAs and MPO-ANCAs has important clinical and pathogenic implications. As dependable immunoassays for PR3-ANCAs and MPO-ANCAs have become broadly available, there is increasing international agreement that high-quality immunoassays are the preferred screening method for the diagnosis of ANCA-associated vasculitis. The present Consensus Statement proposes that high-quality immunoassays can be used as the primary screening method for patients suspected of having the ANCA-associated vaculitides GPA and MPA without the categorical need for IIF, and presents and discusses evidence to support this recommendation.

Concepts: Present, Protease, Wegener's granulomatosis, Pascal, Immunofluorescence, Myeloperoxidase, Anti-neutrophil cytoplasmic antibody, Proteinase 3

24

A loss of humoral tolerance is a hallmark of many autoimmune diseases and the detection of self-reactive antibodies (autoantibodies) of the immunoglobulin G (IgG) isotype is widely used as a biomarker and diagnostic tool. However, autoantibodies might also be present in individuals without autoimmune disease, thus limiting their usefulness as a sole indicator of disease development. Moreover, while clear evidence exists of the pathogenic effects of autoantibodies in mouse model systems, the contribution of autoantibodies to the pathology of many autoimmune diseases has yet to be established. In this Review, the authors discuss the changes in total serum IgG and autoantibody glycosylation that occur during autoimmune disease and how these changes might help to predict disease development in the future. Furthermore, current knowledge of the signals regulating antibody glycosylation and how individual antibody glycoforms could be used to optimize current treatment approaches will be discussed.

Concepts: Immune system, Antibody, Fc receptor, Immunology, Future, Rheumatoid arthritis, Antibodies, Autoimmune diseases

23

The adult and juvenile myositis syndromes, commonly referred to collectively as idiopathic inflammatory myopathies (IIMs), are systemic autoimmune diseases with the hallmarks of muscle weakness and inflammation. Validated, well-standardized measures to assess disease activity, known as core set measures, were developed by international networks of myositis researchers for use in clinical trials. Composite response criteria using weighted changes in the core set measures of disease activity were developed and validated for adult and juvenile patients with dermatomyositis and adult patients with polymyositis, with different thresholds for minimal, moderate and major improvement in adults and juveniles. Additional measures of muscle strength and function are being validated to improve content validity and sensitivity to change. A health-related quality of life measure, which incorporates patient input, is being developed for adult patients with IIM. Disease state criteria, including criteria for inactive disease and remission, are being used as secondary end points in clinical trials. MRI of muscle and immunological biomarkers are promising approaches to discriminate between disease activity and damage and might provide much-needed objective outcome measures. These advances in the assessment of outcomes for myositis treatment, along with collaborations between international networks, should facilitate further development of new therapies for patients with IIM.

Concepts: Immune system, Muscular system, Exercise therapy for idiopathic inflammatory myopathies, Myositis

18

Persistent systemic inflammation, a typical feature of inflammatory rheumatic diseases, is associated with a high cardiovascular risk and predisposes to metabolic disorders and muscle wasting. These disorders can lead to disability and decreased physical activity, exacerbating inflammation and the development of a network of chronic diseases, thus establishing a ‘vicious cycle’ of chronic inflammation. During the past two decades, advances in research have shed light on the role of exercise as a therapy for rheumatic diseases. One of the most important of these advances is the discovery that skeletal muscle communicates with other organs by secreting proteins called myokines. Some myokines are thought to induce anti-inflammatory responses with each bout of exercise and mediate long-term exercise-induced improvements in cardiovascular risk factors, having an indirect anti-inflammatory effect. Therefore, contrary to fears that physical activity might aggravate inflammatory pathways, exercise is now believed to be a potential treatment for patients with rheumatic diseases. In this Review, we discuss how exercise disrupts the vicious cycle of chronic inflammation directly, after each bout of exercise, and indirectly, by improving comorbidities and cardiovascular risk factors. We also discuss the mechanisms by which some myokines have anti-inflammatory functions in inflammatory rheumatic diseases.

Concepts: Inflammation, Medicine, Metabolism, Heart, Cardiovascular disease, Muscle, Physical exercise, Exercise

7

Entheses are the insertion sites of tendons and ligaments to the bone surface and are essential structures for locomotion. Inflammation of the entheses (enthesitis) is a key feature of psoriatic arthritis and spondyloarthritis. To date, our conceptual understanding of enthesitis remains limited. This Review provides an insight into the pathophysiology of enthesitis, addressing the role of biomechanics, prostaglandin E2-mediated vasodilation and the activation of innate immune cells in the initiation phase of enthesitis, as well as the role of entheseal IL-23-responsive cells that augment inflammation by producing pro-inflammatory mediators such as IL-17A, IL-22 and TNF. In addition, the molecular steps that translate inflammation into resident tissue responses, resulting in new bone formation, are discussed. The second part of the article summarizes the clinical features of enthesitis, and the role of clinical and imaging instruments in detecting enthesitis are discussed together with their challenges and limitations. Finally, the Review summarizes the current treatment possibilities for enthesitis based on the aforementioned pathophysiological concepts, focusing on the role of cytokine-blocking agents.

Concepts: Immune system, Bone, Extracellular matrix, Skeletal system, Rheumatoid arthritis, Cartilage, Tumor necrosis factor-alpha, Psoriatic arthritis

5

Fibromyalgia is a common cause of chronic widespread pain, characterized by reduced pressure pain thresholds with hyperalgesia and allodynia. In addition to pain, common symptoms include nonrestorative sleep, fatigue, cognitive dysfunction, stiffness and mood disturbances. The latest research indicates that the dominant pathophysiology in fibromyalgia is abnormal pain processing and central sensitization. Neuroimaging studies have shown that patients with fibromyalgia have similar neural activation to healthy age-matched and gender-matched individuals; however, they have a lower pressure-pain threshold. Polysomnography data has demonstrated that these patients have reduced short-wave sleep and abnormal α-rhythms, suggestive of wakefulness during non-REM (rapid eye movement) sleep. Sleep deprivation in healthy individuals can cause symptoms of fibromyalgia, including myalgia, tenderness and fatigue, suggesting that sleep dysfunction might be not only a consequence of pain, but also pathogenic. Epidemiological studies indicate that poor sleep quality is a risk factor for the development of chronic widespread pain among an otherwise healthy population. Mechanistically, sleep deprivation impairs descending pain-inhibition pathways that are important in controlling and coping with pain. Clinical trials of pharmacological and nonpharmacological therapies have shown that improving sleep quality can reduce pain and fatigue, further supporting the hypothesis that sleep dysfunction is a pathogenic stimulus of fibromyalgia.

Concepts: Medicine, Epidemiology, Sleep, Sleep deprivation, Symptoms, Fibromyalgia, Fatigue, Chronic fatigue syndrome

5

In this article, we present the case for the existence of a subgroup of patients with osteoarthritis (OA) who experience pain with neuropathic features. Recognizing these patients as a distinct subgroup will allow clinicians to improve the management of their symptoms. We discuss the diagnostic criteria for pain to be classed as neuropathic, then systematically examine the applicability of these criteria to the symptoms, signs and pathology of OA. What are the implications for the preclinical development and clinical use of analgesics for OA? How should existing treatment options be reassessed? Differences in the aetiology of OA and the pharmacological sensitivity of patients with OA pain with neuropathic features, compared with other patients with OA, might explain the frequent negative findings of clinical trials of treatments for symptomatic OA. If the global prevalence of OA pain with neuropathic features is accurately represented by reports from small experimental groups of patients, then a substantial unmet need to tailor diagnosis and therapy for these individuals exists.

Concepts: Diagnosis, Hospital, The Canon of Medicine, Avicenna, Greek loanwords, Pain, Philosophy of science, Pre-clinical development