As glucocorticoids and immunosuppressive drugs are non‐specific therapeutic agents that cause many adverse reactions, the development of biologicals aiming to control specific molecular targets is ...anticipated for the treatment of systemic lupus erythematosus (SLE). The antibody targeting B cell‐activating factor belonging to the tumor necrosis factor family (BAFF) belimumab was the first biological approved for SLE. At present, many biologicals, such as anifrolumab (anti‐type I interferon receptor antibody) and ustekinumab (antibody against interleukin 12/23 p40), are in clinical trials. Thus, successful treatments with biologicals targeting “bridging cytokines” produced by dendritic cells, which form a bridge between the innate and acquired immune/autoimmune systems, is of particular interest. Moreover, a phase IIb clinical trial of baricitinib, a low‐molecular‐weight compound targeting Janus kinase 1/2, in patients with SLE revealed that baricitinib was significantly more effective for relieving arthritis and skin manifestations than placebo, and the trial met the primary endpoint. In the future, it is expected that drugs with better efficacy and safety profiles will be used to apply therapeutic strategies, such as precision medicine, in which different molecular target drugs are used for patients classified by their conditions, and to set a therapeutic goal of the discontinuation of glucocorticoids.
The immune system and bone metabolism influence each other. An imbalance in the immune system, resulting in inflammatory stimuli may induce an imbalance in bone turnover via induction of osteoclast ...differentiation and inhibition of osteoblast differentiation, leading to various pathological conditions including osteoporosis. T-cell subsets, helper T (Th)1 and Th17, which activate the immune system, induce osteoclasts, whereas regulatory T (Treg) cells, responsible for immunosuppression, inhibit osteoclastic differentiation. In addition, inflammatory cytokines, such as the tumor necrosis factor (TNF), also cause an imbalance in bone turnover, induction of osteoclasts and inhibition of osteoblasts. Treatments targeting the immune system may regulate abnormalities in bone metabolism, while also controlling immune abnormalities. In rheumatoid arthritis (RA), a representative autoimmune disease, immune abnormality and accompanying prolongation of synovial inflammation cause bone and cartilage destruction, periarticular osteoporosis, and systemic osteoporosis. Joint damage and osteoporosis in RA occur through totally different mechanisms. Stimulation by inflammatory cytokines induces the expression of the receptor activator for nuclear factor-κB ligand (RANKL) in T cells and synovial cells, thereby inducing bone destruction due to osteoblast-independent osteoclast maturation. However, biological products targeting TNF or interleukin-6 not only control disease activity, but also inhibit joint destruction. However, these biological products are not effective for osteoporosis. Conversely, anti-RANKL antibody inhibits osteoporosis and bone destruction, but exerts no influence on RA disease activity. Such differences in therapeutic efficacy may indicate the necessity for rethinking current theories on the mechanism of bone metabolism abnormality and joint destruction. Understanding the mechanisms underlying these pathologies via commonalities existing between the immune system and the metabolic system may lead to the development of new treatments.
Rheumatoid arthritis (RA) is an inflammatory disorder characterized by progressive joint destruction. Recent studies have demonstrated that osteoclasts are responsible for bone destruction in RA. ...Receptor activator of nuclear factor kappa B ligand (RANKL), an osteoclast differentiation factor, belongs to the tumor necrosis factor superfamily and plays a critical role in osteoclast differentiation. RANKL is highly expressed in the synovial tissues in patients with RA and is involved in osteoclast development and thus bone destruction in RA. Denosumab, a specific antibody to human RANKL, efficiently suppressed the progression of bone destruction in patients with RA in a randomized controlled study and is considered a putative therapeutic option for RA.
Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting the joints and is associated with significant levels of disability and reduced quality of life. Janus kinase (JAK) ...inhibitors are a relatively new class of small molecule oral treatments and offer an alternative for patients with RA who do not respond to conventional or biologic therapy. Upadacitinib is a JAK inhibitor engineered to be selective for JAK1, and has recently been approved for use in patients with moderate-to-severe RA. The purpose of this article is to provide a comprehensive review of upadacitinib, including preclinical development and characterization, phase I and II studies, and the phase III SELECT program. Ongoing trials of upadacitinib in additional indications, including spondyloarthritis, inflammatory bowel disease, and atopic dermatitis, are also discussed.
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and joint destruction. However, the combined use of synthetic disease-modifying anti-rheumatic drug ...(DMARD) such as methotrexate and a biological DMARD targeting tumour necrosis factor (TNF) has revolutionized treatment of RA. Clinical remission is a realistic target to treat and the maintenance of remission has produced significant improvements in structural and function outcomes. However, biological DMARDs are limited to intravenous or subcutaneous uses and orally available small but strong products have been developed. The multiple cytokines and cell surface molecules bind to receptors, resulting in the activation of various signalling, including phosphorylation of kinase proteins. Among multiple kinases, Janus kinase (JAK) plays pivotal roles in the pathological processes of RA. Tofacitinib, a small product targeting JAK, inhibits phosphorylation of JAK1 and JAK3, subsequent Stat1 and expression of Stat1-inducible genes, which contribute to efficient propagation of its anti-inflammatory effects for the treatment of RA. The primary targets of tofacitinib are dendritic cells, CD4(+) T cells such as Th1 and Th17 and activated B cells which leads to multi-cytokine targeting. Six global phase 3 studies revealed that oral administration of 5 or 10 mg tofacitinib was significantly effective than placebo with or without methotrexate in active RA patients with methotrexate-naïve, inadequately responsive to methotrexate or TNF-inhibitors. Therapeutic efficacy of tofacitinib was observed in a short term after administration and was as strong as adalimumab, a TNF-inhibitor. The most commonly observed adverse events were related to infection, hematologic, hepatic and renal disorders and association of tofacitinib with carcinogenicity and infections remains debated. Further investigation on post-marketing survey would help us understand the positioning of this drug.
In rheumatoid arthritis, a representative systemic autoimmune disease, immune abnormality and accompanying persistent synovitis cause bone and cartilage destruction and systemic osteoporosis. ...Biologics targeting tumor necrosis factor, which plays a central role in the inflammatory process, and Janus kinase inhibitors have been introduced in the treatment of rheumatoid arthritis, making clinical remission a realistic treatment goal. These drugs can prevent structural damage to bone and cartilage. In addition, osteoporosis, caused by factors such as menopause, aging, immobility, and glucocorticoid use, can be treated with bisphosphonates and the anti-receptor activator of the nuclear factor-κB ligand antibody. An imbalance in the immune system in rheumatoid arthritis induces an imbalance in bone metabolism. However, osteoporosis and bone and cartilage destruction occur through totally different mechanisms. Understanding the mechanisms underlying osteoporosis and joint destruction in rheumatoid arthritis leads to improved care and the development of new treatments.
Biological agents targeting tumour necrosis factor (TNF) have revolutionised the treatment of rheumatoid arthritis (RA) and clinical remission has become a realistic treatment goal. Discontinuing ...anti-TNF therapy after sustained remission has emerged as an important area of investigation in rheumatology from the risk-benefit point of view, including health economic considerations. However, there is little information as to whether 'biologic-free remission' is possible after sustained remission following intensive treatment with TNF inhibitors in RA. European studies such as BeSt and OPTIMA in patients with early RA and Japanese studies such as remission induction by remicade in patients with RA and HONOR in patients with long-standing RA encountered during routine clinical practice have shown that, after a reduction in disease activity to clinical remission or low disease activity by infliximab or adalimumab in combination with methotrexate, patients can successfully remain in clinical remission without TNF inhibitors with no radiological and functional damage progression of articular destruction. Experimental findings in TNF-deficient mouse models suggest that TNF inhibitors may change the disease process of RA and bring about the potential of immunological remission, raising the possibility of a 'treatment holiday' of TNF inhibitors after intensive treatment.
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However, the combined use of ...methotrexate, a synthetic disease-modifying antirheumatic drug (DMARD), and biologic DMARD has revolutionized treatment of RA. Clinical remission is now realistic targets, achieved by a large proportion of RA patients, and rapid and appropriate induction of remission by intensive treatment with biological DMARD and methotrexate is prerequisite to halt joint damage and functional disabilities. However, biological DMARD is limited to intravenous or subcutaneous uses and orally available small but strong molecules have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active patients with methotrexatenaïve, inadequately responsive to methotrexate or tumor necrosis factor (TNF)-inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor. Meanwhile, association of tofacitinib on carcinogenicity and malignancy is under debate and further investigation on post-marketing survey would be warranted. On the other hand, discontinuation of a biological DMARD without disease flare is our next goal and desirable from the standpoint of risk reduction and cost effectiveness, especially for patients with clinical remission. Recent reports indicate that more than half of early RA patients could discontinue TNF-targeted biological DMARD without clinical flare and functional impairment after obtaining clinical remission. Contrarily, for established RA, fewer patients sustained remission after the discontinuation of biological DMARD and "deep remission" at the discontinuation was a key factor to keep the treatment holiday of biological DMARD.
The population of people in Japan over 65 years old is expected to exceed 30% by 2025. As the society ages, there are not only healthy workers and employers, but also an increasing number of diseased ...or injured workers. Falls, the most common occupational hazard, increase in incidence with age. The management of osteoporosis and prevention of bone fractures from falls are emerging in elderly female workers, to reduce the loss of work productivity. Rheumatoid arthritis is a representative musculoskeletal disease that causes functional decline because of joint damage mainly in working women, but appropriate treatment improves disease activity and work productivity in workers with rheumatoid arthritis. It is also important not only to digitize subjective information by converting it into digital form (digitization), but also to digitalize the physiological information related to health, labor and disease (digitalization). In the future, artificial intelligence (AI) will be able to analyze vast amounts of physiological information (big data) obtained from workers and patients via the Internet of things (IoT), which will improve the information value linked to health promotion and optimal treatment practices, and contribute to the Digital transformation (DX).
A phase 3 trial of anifrolumab, a monoclonal antibody to type I interferon receptor subunit 1, showed benefit in a composite primary end point of lupus scores. A previous phase 3 trial failed to meet ...its primary objective but showed an effect in secondary end points.
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