Imaging techniques such as ultrasonography and MRI have gained ground in the diagnosis and management of inflammatory arthritis, as these imaging modalities allow a sensitive assessment of musculoskeletal inflammation and damage. However, these techniques cannot discriminate between disease subsets and are currently unable to deliver an accurate prediction of disease progression and therapeutic response in individual patients. This major shortcoming of today's technology hinders a targeted and personalized patient management approach. Technological advances in the areas of high-resolution imaging (for example, high-resolution peripheral quantitative computed tomography and ultra-high field MRI), functional and molecular-based imaging (such as chemical exchange saturation transfer MRI, positron emission tomography, fluorescence optical imaging, optoacoustic imaging and contrast-enhanced ultrasonography) and artificial intelligence-based data analysis could help to tackle these challenges. These new imaging approaches offer detailed anatomical delineation and an in vivo and non-invasive evaluation of the immunometabolic status of inflammatory reactions, thereby facilitating an in-depth characterization of inflammation. By means of these developments, the aim of earlier diagnosis, enhanced monitoring and, ultimately, a personalized treatment strategy looms closer.

Xanthine oxidase inhibitors such as allopurinol and febuxostat have been the mainstay urate-lowering therapy (ULT) for treating hyperuricaemia in patients with gout. However, not all patients receiving oral ULT achieve the target serum urate level, in part because some patients cannot tolerate, or have actual or misconceived contraindications to, their use, mainly due to comorbidities. ULT dosage is also limited by formularies and clinical inertia. This failure to sufficiently lower serum urate levels can lead to difficult-to-treat or uncontrolled gout, usually due to poorly managed and/or under-treated gout. In species other than humans, uricase (urate oxidase) converts urate to allantoin, which is more soluble in urine than uric acid. Exogenic uricases are an exciting therapeutic option for patients with gout. They can be viewed as enzyme replacement therapy. Uricases are being used to treat uncontrolled gout, and can achieve rapid reduction of hyperuricaemia, dramatic resolution of tophi, decreased chronic joint pain and improved quality of life. Availability, cost and uricase immunogenicity have limited their use. Uricases could become a leading choice in severe and difficult-to-treat gout as induction and/or debulking therapy (that is, for lowering of the urate pool) to be followed by chronic oral ULT. This Review summarizes the evidence regarding available uricases and those in the pipeline, their debulking effect and their outcomes related to gout and beyond.

The concept of immunological memory was demonstrated in antiquity when protection against re-exposure to pathogens was observed during the plague of Athens. Immunological memory has been linked with the adaptive features of T and B cells; however, in the past decade, evidence has demonstrated that innate immune cells can exhibit memory, a phenomenon called 'innate immune memory' or 'trained immunity'. Innate immune memory is currently being defined and is transforming our understanding of chronic inflammation and autoimmunity. In this Review, we provide an up-to-date overview of the memory-like features of innate immune cells in inflammatory arthritis and the crosstalk between chronic inflammatory milieu and cell reprogramming. Aberrant pro-inflammatory signalling, including cytokines, regulates the metabolic and epigenetic reprogramming of haematopoietic progenitors, leading to exacerbated inflammatory responses and osteoclast differentiation, in turn leading to bone destruction. Moreover, imprinted memory on mature cells including terminally differentiated osteoclasts alters responsiveness to therapies and modifies disease outcomes, commonly manifested by persistent inflammatory flares and relapse following medication withdrawal.

To inform an international task force about current evidence on Treat to Target (T2T) strategies in PMR and GCA.

Immune-mediated inflammatory diseases (IMIDs) are responsible for substantial global disease burden and associated health-care costs. Traditional models of research and service delivery silo their management within organ-based medical disciplines. Very often patients with disease in one organ have comorbid involvement in another, suggesting shared pathogenic pathways. Moreover, different IMIDs are often treated with the same drugs (including glucocorticoids, immunoregulators and biologics). Unlocking the cellular basis of these diseases remains a major challenge, leading us to ask why, if these diseases have so much in common, they are not investigated in a common manner. A tissue-based, cellular understanding of inflammation might pave the way for cross-disease, cross-discipline basket trials (testing one drug across two or more diseases) to reduce the risk of failure of early-phase drug development in IMIDs. This new approach will enable rapid assessment of the efficacy of new therapeutic agents in cross-disease translational research in humans.

The incidence of rheumatic diseases such as rheumatoid arthritis and osteoarthritis and injuries to articular cartilage that lead to osteochondral defects is predicted to rise as a result of population ageing and the increase in high-intensity physical activities among young and middle-aged people. Current treatments focus on the management of pain and joint functionality to improve the patient's quality of life, but curative strategies are greatly desired. In the past two decades, the therapeutic value of mesenchymal stromal cells (MSCs) has been evaluated because of their regenerative potential, which is mainly attributed to the secretion of paracrine factors. Many of these factors are enclosed in extracellular vesicles (EVs) that reproduce the main functions of parental cells. MSC-derived EVs have anti-inflammatory, anti-apoptotic as well as pro-regenerative activities. Research on EVs has gained considerable attention as they are a potential cell-free therapy with lower immunogenicity and easier management than whole cells. MSC-derived EVs can rescue the pathogenetic phenotypes of chondrocytes and exert a protective effect in animal models of rheumatic disease. To facilitate the therapeutic use of EVs, appropriate cell sources for the production of EVs with the desired biological effects in each disease should be identified. Production and isolation of EVs should be optimized, and pre-isolation and post-isolation modifications should be considered to maximize the disease-modifying potential of the EVs.

The aim of this systematic review and meta-analysis was to summarize current evidence regarding body composition (BC) in SSc in order to gain new insights and improve clinical care in the context of the nutritional status of SSc patients.

Janus kinases (JAKs) are a family of cytosolic tyrosine kinases that regulate cytokine signal transduction, including cytokines involved in a range of inflammatory diseases, such as RA, psoriasis, atopic dermatitis and IBD. Several small-molecule JAK inhibitors (JAKis) are now approved for the treatment of various immune-mediated inflammatory diseases. There are, however, key differences between these agents that could potentially translate into unique clinical profiles. Each JAKi has a unique chemical structure, resulting in a distinctive mode of binding within the catalytic cleft of the target JAK, and giving rise to distinct pharmacological characteristics. In addition, the available agents have differing selectivity for JAK isoforms, as well as off-target effects against non-JAKs. Other differences include effects on haematological parameters, DNA damage repair, reproductive toxicity and metabolism/elimination. Here we review the pharmacological profiles of the JAKis abrocitinib, baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib.

Calprotectin (CLP) is a calcium-binding protein produced by neutrophils and monocytes in the course of inflammation. Today, the role of faecal CLP in chronic IBD is well known, but in recent years attention has shifted towards circulating CLP. In fact, this molecule can be measured in different biological fluids: blood, saliva and urine, using different analytic methods that are described in this review. Furthermore, different data confirm the relevant role of serum CLP in autoimmune diseases. In this review we will highlight the correlation between high levels of circulating CLP and specific autoantibodies of major autoimmune pathologies paving the way to the employment of CLP measurement as useful biomarker for monitoring outcome in different pathologies.

The relationship between FMF and pregnancy outcomes remains unclear. This systematic review and meta-analysis aimed to clarify this association.

Interleukin-6 (IL-6) is one of the cytokines implicated in murine and human SLE. Only a few small studies have investigated IL-6 inhibition in human SLE. Currently, there are no studies registered in clinicaltrials.gov to assess the IL-6 targeted therapy in SLE, yet its role in the future remains to be defined. This narrative review analyses these and potential areas of future studies with IL-6 targeted therapy in SLE.

The cytokine TNF signals via two distinct receptors, TNF receptor 1 (TNFR1) and TNFR2, and is a central mediator of various immune-mediated diseases. Indeed, TNF-neutralizing biologic drugs have been in clinical use for the treatment of many inflammatory pathological conditions, including various rheumatic diseases, for decades. TNF has pleiotropic effects and can both promote and inhibit pro-inflammatory processes. The integrated net effect of TNF in vivo is a result of cytotoxic TNFR1 signalling and the stimulation of pro-inflammatory processes mediated by TNFR1 and TNFR2 and also TNFR2-mediated anti-inflammatory and tissue-protective activities. Inhibition of the beneficial activities of TNFR2 might explain why TNF-neutralizing drugs, although highly effective in some diseases, have limited benefit in the treatment of other TNF-associated pathological conditions (such as graft-versus-host disease) or even worsen the pathological condition (such as multiple sclerosis). Receptor-specific biologic drugs have the potential to tip the balance from TNFR1-mediated activities to TNFR2-mediated activities and enable the treatment of diseases that do not respond to current TNF inhibitors. Accordingly, a variety of reagents have been developed that either selectively inhibit TNFR1 or selectively activate TNFR2. Several of these reagents have shown promise in preclinical studies and are now in, or approaching, clinical trials.

Polymyositis (PM) and dermatomyositis (DM) are rare idiopathic inflammatory myopathies (IIM). Myocardial involvement in patients with IIM is an unfavorable prognostic factor and one of the most common cause of mortality in this group of patients. The purpose of this review is to present current knowledge on cardiovascular manifestations observed in IIM. Data published in English until December 2021 were selected. Clinical symptoms suggesting cardiac involvement are non-specific and require a differential diagnosis in accordance with cardiological guidelines. Troponin I is specific to cardiac injury and should be preferred to other markers to evaluate the myocardium in IIM. Abnormalities in electrocardiography are common in IIM, especially non-specific changes of the ST-T segment. In standard echocardiography left ventricular diastolic dysfunction is reported frequently. New diagnostic technologies can reveal clinically silent myocardial abnormalities. However, the prognostic value of subclinical impairment of myocardial function require further studies.

Although the pathological mechanisms involved in osteoarthritis (OA) and rheumatoid arthritis (RA) are different, the onset and progression of both diseases are associated with several analogous clinical manifestations, inflammation, and immune mechanisms. In both diseases, cartilage destruction is mediated by matrix metalloproteinases (MMPs) synthesized by chondrocytes and synovium fibroblasts. This review aims to summarize recent articles regarding the role of MMPs in OA and RA, as well as the possible methods of targeting MMPs to alleviate the degradation processes taking part in OA and RA. The novel experimental MMP-targeted treatments in OA and RA are MMP inhibitors eg. 3-B2, taraxasterol, and naringin, while other treatments aim to silence miRNAs, lncRNAs, or transcription factors. Additionally, other recent MMP-related developments include gene polymorphism of MMPs, which have been linked to OA susceptibility, and the MMP-generated neoepitope of CRP, which could serve as a biomarker of OA progression.

The authors of the study assessed the emotional and cognitive state of geriatric patients during the COVID-19 pandemic and tried to answer the question: were there any differences in this state in geriatric patients at different stages of the pandemic?

Sleep has a homeostatic role in the regulation of the immune system and serves to constrain activation of inflammatory signalling and expression of cellular inflammation. In patients with rheumatoid arthritis (RA), a misaligned inflammatory profile induces a dysregulation of sleep-wake activity, which leads to excessive inflammation and the induction of increased sensitivity to pain. Given that multiple biological mechanisms contribute to sleep disturbances (such as insomnia), and that the central nervous system communicates with the innate immune system via neuroendocrine and neural effector pathways, potential exists to develop prevention opportunities to mitigate the risk of insomnia in RA. Furthermore, understanding these risk mechanisms might inform additional insomnia treatment strategies directed towards steering and reducing the magnitude of the inflammatory response, which together could influence outcomes of pain and disease activity in RA.

Vaccines are important for protecting individuals at increased risk of severe infections, including patients undergoing DMARD therapy. However, DMARD therapy can also compromise the immune system, leading to impaired responses to vaccination. This Review focuses on the impact of DMARDs on influenza and SARS-CoV-2 vaccinations, as such vaccines have been investigated most thoroughly. Various data suggest that B cell depletion therapy, mycophenolate mofetil, cyclophosphamide, azathioprine and abatacept substantially reduce the immunogenicity of these vaccines. However, the effects of glucocorticoids, methotrexate, TNF inhibitors and JAK inhibitors on vaccine responses remain unclear and could depend on the dosage and type of vaccination. Vaccination is aimed at initiating robust humoral and cellular vaccine responses, which requires efficient interactions between antigen-presenting cells, T cells and B cells. DMARDs impair these cells in different ways and to different degrees, such as the prevention of antigen-presenting cell maturation, alteration of T cell differentiation and selective inhibition of B cell subsets, thus inhibiting processes that are necessary for an effective vaccine response. Innovative modified vaccination strategies are needed to improve vaccination responses in patients undergoing DMARD therapy and to protect these patients from the severe outcomes of infectious diseases.

Systemic lupus erythematosus (SLE) is a disease of high unmet therapeutic need. The challenge of accurately measuring clinically meaningful responses to treatment has hindered progress towards positive outcomes in SLE trials, impeding the approval of potential new therapies. Current primary end points used in SLE trials are based on legacy disease activity measures that were neither specifically designed for the clinical trial context, nor developed according to contemporary recommendations for clinical outcome assessments (COAs), such as that substantial patient input should be incorporated into their design. The Treatment Response Measure for SLE (TRM-SLE) Taskforce is a global collaboration of SLE clinician-academics, patients and patient representatives, industry partners and regulatory experts, established to realize the goal of developing a new COA for SLE clinical trials. The aim of this project is a novel COA designed specifically to measure treatment effects that are clinically meaningful to patients and clinicians, and intended for implementation in a trial end point that supports regulatory approval of novel therapeutic agents in SLE. This Consensus Statement reports the first outcomes of the TRM-SLE project, including a structured process for TRM-SLE development.

The field of rheumatology has experienced dozens of novel drug approvals in the past two and a half decades, but the regulatory mechanisms underpinning these decisions are not well understood. In the USA, the Food and Drug Administration (FDA) evaluates the safety and efficacy of novel drugs through the New Drug Application (NDA) process. When additional content expertise is required to evaluate scientific or technical matters, the FDA may convene Human Drug Advisory Committees. To better understand the landscape of rheumatology NDAs and the FDA use of advisory committees, we performed a review of all rheumatic disease drug applications from 1996 to 2021 that were granted approval by the FDA. Our review identified 31 NDAs, seven of which utilized an advisory committee. The indications for using advisory committees and their influence on ultimate approvals was not clear. Recommendations to improve transparency and increase public trust in FDA decisions are provided.

Spondyloarthritis (SpA) is characterized by the infiltration of innate and adaptive immune cells into entheses and bone marrow. Molecular, cellular and imaging evidence demonstrates the presence of bone marrow inflammation, a hallmark of SpA. In the spine and the peripheral joints, bone marrow is critically involved in the pathogenesis of SpA. Evidence suggests that bone marrow inflammation is associated with enthesitis and that there are roles for mechano-inflammation and intestinal inflammation in bone marrow involvement in SpA. Specific cell types (including mesenchymal stem cells, innate lymphoid cells and γδ T cells) and mediators (Toll-like receptors and cytokines such as TNF, IL-17A, IL-22, IL-23, GM-CSF and TGFβ) are involved in these processes. Using this evidence to demonstrate a bone marrow rather than an entheseal origin for SpA could change our understanding of the disease pathogenesis and the relevant therapeutic approach.