Rheumatoid arthritis is a chronic, systemic autoimmune disease manifested primarily as inflammatory arthritis, typically involving the small joints of the hands and feet. It can lead to severe ...disability and death.
Immune-mediated inflammatory diseases are common and clinically diverse. Although they are currently incurable, the therapeutic armamentarium for immune-mediated inflammatory diseases has been ...transformed in the past two decades. We have moved from the wide application of broad-spectrum immune modulators to the routine use of agents with exquisite specificity, arising from monoclonal and molecular biotechnology and more recently from highly targeted medicinal chemistry. Here we describe key advances and lessons that drove this remarkable progress and thereafter reflect on the next steps in this ongoing journey.
Patients with rheumatoid arthritis (RA) have historically developed progressive damage of articular bone and cartilage, which correlates with disability over time. In addition, these patients are ...prone to periarticular and systemic bone loss, carrying additional morbidity. In contrast to what is seen in many other rheumatic diseases, the impact of inflammation on bone in RA is uniquely destructive. Loss of articular bone (erosions) and periarticular bone (demineralization) is a result of excessive bone resorption and markedly limited bone formation. There has been tremendous progress in preventing net bone loss in RA with the advent of disease-modifying agents, including biologic agents and small molecules, that both limit inflammation and may have a direct impact on the prevention of cytokine- and antibody-driven osteoclastogenesis. However, repair of existing bone erosions, although feasible, is observed infrequently. Lack of repair is a consequence of suppression of osteoblast function and bone formation by some of the same mechanisms that promote osteoclastogenesis and bone resorption. As new agents are introduced to control inflammation in RA, and novel mechanisms to target synovitis are identified, it may be possible in the future to fully repair damaged bone.
Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor in lymphocyte activation, acting as an immune checkpoint to prevent the continued activation of T cells after an immune ...response and to maintain peripheral immune tolerance. PD-1 is a marker of antigen-experienced T cells. With sustained T-cell stimulation — as occurs in tumor microenvironments — PD-1 is expressed by anergic and regulatory CD4+ T cells and by exhausted CD8+ T cells. The expression of PD-1 by helper T cells is necessary for their functional interaction with B cells.
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In this issue of the
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Tuttle and colleagues report findings . . .
The past decade has observed an explosion of new information regarding the impact of inflammation on bone. In rheumatic diseases, several factors that act as both immune modulators and regulators of ...bone homeostasis have been shown to mediate an imbalance in bone resorption and bone formation resulting in joint degeneration. In rheumatoid arthritis (RA), focal bone loss is due to excess bone resorption by osteoclasts. Resorption is mediated in part by increased local expression of the cytokine receptor activator of nuclear factor-κB ligand (RANKL) compared with expression of its decoy receptor osteoprotegerin (OPG). Bone formation by osteoblasts is also impaired at erosion sites in RA, and inhibitors of the canonical Wingless (Wnt) signaling pathway, including DKK1, have been implicated in the suppression of normal osteoblast function at these sites. Inhibition of DKK1 in an animal model of RA attenuated bone erosion by increasing OPG expression as well as promoting bone formation. In contrast to RA, inflammation in the spondyloarthropathies often results in excess periosteal bone formation, highlighting that the net impact of inflammation on bone is specific to the site at which inflammation occurs, and the cell types, cytokines, and factors present within the local bone microenvironment. This fertile area of research bears watching for the identification of novel targets for the prevention of abnormal bone remodeling in inflammatory diseases.
Local delivery of therapeutics for the treatment of inflammatory arthritis (IA) is limited by short intra-articular half-lives. Since IA severity often fluctuates over time, a local drug delivery ...method that titrates drug release to arthritis activity would represent an attractive paradigm in IA therapy. Here we report the development of a hydrogel platform that exhibits disassembly and drug release controlled by the concentration of enzymes expressed during arthritis flares. In vitro, hydrogel loaded with triamcinolone acetonide (TA) releases drug on-demand upon exposure to enzymes or synovial fluid from patients with rheumatoid arthritis. In arthritic mice, hydrogel loaded with a fluorescent dye demonstrates flare-dependent disassembly measured as loss of fluorescence. Moreover, a single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduces arthritis activity in the injected paw. Together, our data suggest flare-responsive hydrogel as a promising next-generation drug delivery approach for the treatment of IA.
Dysregulated bone remodeling occurs when there is an imbalance between bone resorption and bone formation. In rheumatic diseases, including rheumatoid arthritis (RA) and seronegative ...spondyloarthritis, systemic and local factors disrupt the process of physiologic bone remodeling. Depending upon the local microenvironment, cell types, and local mechanical forces, inflammation results in very different effects on bone, promoting bone loss in the joints and in periarticular and systemic bone in RA and driving bone formation at enthesial and periosteal sites in diseases such as ankylosing spondylitis (AS), included within the classification of axial spondyloarthritis. There has been a great deal of interest in the role of osteoclasts in these processes and much has been learned over the past decade about osteoclast differentiation and function. It is now appreciated that osteoblast-mediated bone formation is also inhibited in the RA joint, limiting the repair of erosions. In contrast, osteoblasts function to produce new bone in AS. The Wnt and BMP signaling pathways have emerged as critical in the regulation of osteoblast function and the outcome for bone in rheumatic diseases, and these pathways have been implicated in both bone loss in RA and bone formation in AS. These pathways provide potential novel approaches for therapeutic intervention in diseases in which inflammation impacts bone.
Objective
To provide guidance to rheumatology providers on the management of adult rheumatic disease in the context of the coronavirus disease 2019 (COVID‐19) pandemic.
Methods
A task force, ...including 10 rheumatologists and 4 infectious disease specialists from North America, was convened. Clinical questions were collated, and an evidence report was rapidly generated and disseminated. Questions and drafted statements were reviewed and assessed using a modified Delphi process. This included asynchronous anonymous voting by email and webinars with the entire panel. Task force members voted on agreement with draft statements using a 1–9‐point numerical scoring system, and consensus was determined to be low, moderate, or high based on the dispersion of votes. For approval, median votes were required to meet predefined levels of agreement (median values of 7–9, 4–6, and 1–3 defined as agreement, uncertainty, or disagreement, respectively) with either moderate or high levels of consensus.
Results
Draft guidance statements approved by the task force have been combined to form final guidance.
Conclusion
These guidance statements are provided to promote optimal care during the current pandemic. However, given the low level of available evidence and the rapidly evolving literature, this guidance is presented as a “living document,” and future updates are anticipated.
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