Frontiers in Medicine is delighted to present the ‘Reviews in’ series of Research Topics. Reviews in is a series being launched across Frontiers in Medicine’s sections which aims to publish high-quality review articles on key topics within the field. The goal of this series is to highlight recent advances within the field, whilst emphasizing important directions and new possibilities for future inquiries. This Research Topic welcomes full-length, mini and systematic review papers on topics within Rheumatology. New articles will be added to this collection as they are published. Please note that manuscripts consisting solely of bioinformatics or computational analyses of public genomic or transcriptomic databases will not be considered for this collection

University of Debrecen

Karada Terrace Ebina

University of Liège

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Frontiers in Medicine

Rheumatology

Reviews in Rheumatology

Rheumatic diseases and musculoskeletal disorders are among the leading causes of disability worldwide. It is therefore essential to promote medical and scientific advances in these diseases (<a href="#B1">1</a>). This is why we initiated the special edition research series in Frontiers in Medicine called “Review in rheumatology.” This series aims to overview the most recent advances in the physiopathology, diagnosis, and treatment of rheumatic diseases and musculoskeletal disorders. The authors were also invited to propose future directions for basic and clinical research. Four published papers were dedicated to rheumatoid arthritis, one to systemic lupus erythematosus, and finally one on frozen shoulder. These pathologies have several pathophysiological mechanisms in common, such as the activation of the innate immune response, and local and systemic inflammation. Control inflammation is a key target in the management of these pathologies not only to control symptoms but also to prevent connective tissue degradation. The knowledge of inflammation has strongly progressed during the last decades. Macrophage polarization, mitochondria homeostasis, intestinal or oral dysbiosis, cell senescence, and environmental factors are among the most investigated possible therapeutic target to resolve inflammation chronicity and therapeutic failure in patients with severe rheumatic diseases like rheumatoid arthritis (RA).Difficult-to-treat RA (D2T RA) is a specific disease state that affects 3%−10% of RA patients. This disease state can be defined as the persistence of signs suggestive of active/progressive disease after conventional synthetic disease-modifying antirheumatic drug therapy (csDMARDs) and at least two targeted biologic and synthetic DMARDs (b/ts) with different mechanisms of action. <a href="https://doi.org/10.3389/fmed.2022.1049875">Watanabe et al.</a> discussed this particular unresolved disease state and proposed a strategy to prevent patients from developing this D2T RA. According to them, the treatment of D2T RA requires a combination of pharmacological and non-pharmacological interventions. Correcting modifiable risk factors, such as smoking, obesity, poor compliance, and periodontitis, is also important in suppressing the development of RA D2T. Starting early intervention with b/tsDMARDs and selecting the appropriate b/tsDMARDs are two other essential actions to prevent the onset of this particular disease condition, especially for patients with highly active disease who have an inadequate response to high-dose of methotrexate.Osteoimmunology concepts in RA account for the molecular crosstalk between the immune and skeletal systems, resulting in the disruption of bone remodeling. In their review, <a href="https://doi.org/10.3389/fmed.2022.962969">Sakthiswary et al.</a> summarized the molecular mechanisms involved in bone loss associated with RA with particular attention to the aryl-hydrocarbon receptor (Ahr) which acts on this process through the generation of Th17 and the RANKL/OPG balance. A higher RANKL/OPG ratio is associated with increased radiographic damage in RA patients, suggesting that controlling this balance may prevent bone resorption in RA.Interleukin-34 (IL-34) is a macrophage growth factor detected at high levels in synovial fluid (SF), synovial cells, and serum of RA patients. The role of this cytokine in controlling the inflammatory response remains controversial. For some authors, it is pro-inflammatory and for others anti-inflammatory. IL-34 is also proposed as a biomarker of RA remission due to a strong correlation between IL-34 and RA relapse after discontinuation of antirheumatic therapy. In this article, <a href="https://doi.org/10.3389/fmed.2022.1078350">Park et al.</a> amalgamate information surrounding the involvement of IL-34 in the pathogenesis of RA, in particular regarding how IL-34 integrates into the mechanisms of macrophage and T-cell activation seen in RA.Modulation of mitochondrial homeostasis and repair of mitochondrial damage to treat RA is a very promising therapeutic approach. In their article, <a href="https://doi.org/10.3389/fmed.2022.1017650">Cui et al.</a> address several research ways such as the modulation of biogenesis, function, and autophagy of mitochondria. To date, most frontier anti-rheumatic drugs commonly used clinically, like methotrexate, maintain mitochondrial homeostasis. In contrast, many targeted biological therapies for RA cannot directly target mitochondria. Rather, they block cytokine signaling pathways, especially inflammatory cytokine signaling, which has a powerful effect on mitochondrial biology. Therefore, molecules targeting specifically mitochondria could open up new therapeutic avenues.Systemic lupus erythematosus (SLE) is a disease associated with a high risk of mortality mainly due to lupus nephritis. Diagnostic delays and misdiagnoses are common in SLE. Early diagnosis and effective treatment may prevent long-term complications that cause increased morbidity and mortality. <a href="https://doi.org/10.3389/fmed.2021.682544">Yavuz and Lipsky</a> discussed the discovery and the relevance of clinical and molecular markers for early diagnosis, monitoring of disease, and phenotyping of the SLE patient to deliver the appropriate therapy based on specific dysregulated molecular pathways.Finally, <a href="https://doi.org/10.3389/fmed.2021.663703">de la Serna et al.</a> proposed an intriguing paper about the physiopathology of a frozen shoulder. They hypothesize that idiopathic frozen shoulder and comorbid conditions such as diabetes share common pathophysiological mechanisms, such as the accumulation of advanced glycation end products derived from insulin resistance and low-grade inflammation. This hypothesis opens new therapeutic perspectives. Besides the core treatment of the freezing phase combining corticosteroids infiltration, manual mobilization, and physiotherapy, the authors suggest the administration of lactoferrin, pre-probiotics, glutamine supplementation, curcumin, resveratrol, EGCG, soy isoflavones, etc., as potential modulators of the disease, although further studies are warranted.In conclusion, the articles published in this Research Topic report the most recent knowledge on the pathophysiology of some of the most debilitating inflammatory rheumatic diseases. They identify exciting future directions for their diagnosis and treatment. We sincerely hope that readers will enjoy their reading and that it will be inspiring for their clinical and research activity.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.YH was employed by the Osteoarthritis Foundation. YH is the founder and executive president of Artialis SA. He has also received consulting fees from Grunenthal, Tilman, Expanscience, Genequine, Allegro, Thuasne, Nestl&#xe9;, and Ibsa.The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Editorial: Reviews in rheumatology

Rheumatoid arthritis (RA) is a chronic autoimmune disease with a multifaceted etiology, which primarily affects and results in the deterioration of the synovium of patients. While the exact etiology of RA is still largely unknown, there is growing interest in the cytokine interleukin-34 (IL-34) as a driver or modulator of RA pathogenesis on the grounds that IL-34 is drastically increased in the serum and synovium of RA patients. Several studies have so far revealed the relationship between IL-34 levels and RA disease progression. Nevertheless, the significance and role of IL-34 in RA have remained ambiguous, as illustrated by two most recent studies, which reported contrasting effects of genetic IL-34 deletion in RA. Of note, IL-34 is a macrophage growth factor and is increasingly perceived as a master regulator of T-cell responses in RA via macrophage-dependent as well as T cell-intrinsic mechanisms. In this regard, several studies have demonstrated that IL-34 potentiates helper T-cell (Th) responses in RA, whereas studies also suggested that IL-34 alleviates synovial inflammation, potentially by inducing regulatory T-cells (Treg). Herein, we provide an overview of the current understanding of IL-34 involvement in RA and outline IL-34-mediated mechanisms in regulating T-cell responses in RA.

Rheumatoid arthritis (RA) is a chronic autoimmune disease with a multifaceted etiology, which primarily affects and results in the deterioration of the synovium of patients. While the exact etiology of RA is still largely unknown, there is growing interest in the cytokine interleukin-34 (IL-34) as a driver or modulator of RA pathogenesis on the grounds that IL-34 is drastically increased in the serum and synovium of RA patients. Several studies have so far revealed the relationship between IL-34 levels and RA disease progression. Nevertheless, the significance and role of IL-34 in RA have remained ambiguous, as illustrated by two most recent studies, which reported contrasting effects of genetic IL-34 deletion in RA. Of note, IL-34 is a macrophage growth factor and is increasingly perceived as a master regulator of T-cell responses in RA via macrophage-dependent as well as T cell-intrinsic mechanisms. In this regard, several studies have demonstrated that IL-34 potentiates helper T-cell (Th) responses in RA, whereas studies also suggested that IL-34 alleviates synovial inflammation, potentially by inducing regulatory T-cells (Treg). Herein, we provide an overview of the current understanding of IL-34 involvement in RA and outline IL-34-mediated mechanisms in regulating T-cell responses in RA.

Interleukin-34-regulated T-cell responses in rheumatoid arthritis

Over the past several decades, the treatment of rheumatoid arthritis (RA) has advanced significantly, and clinical, structural, and functional remission are achievable therapeutic goals. However, a substantial number of patients show resistance to multiple drugs. In particular, patients whose disease activity cannot be controlled despite the use of two or more biological disease-modifying antirheumatic drugs (DMARDs) or targeted synthetic DMARDs (tsDMARDs) with different mechanisms of action (MOA) have recently been referred to as having difficult-to-treat RA (D2T RA). D2T RA is a heterogeneous and multifactorial disease state, and the major problems are uncontrolled disease activity and decreased quality of life, as well as the economic burden due to frequent healthcare utilization and multiple admissions. Since the concept of D2T RA is relatively new and publication regarding D2T RA is limited, the mechanism underlying DMARD inefficacy and which factors form a “difficult-to-treat” state in such patients are not yet fully understood. It is also possible that factors contributing to D2T RA may differ by patient, sex, country, and race. The present Mini Review introduces the current concept and unsolved problems of D2T RA, including the definition, prevalence, and factors contributing to D2T RA. We then discuss the management and therapeutic strategies for D2T RA. Finally, we explore a clinical approach to prevent patients from developing D2T RA.

Over the past several decades, the treatment of rheumatoid arthritis (RA) has advanced significantly, and clinical, structural, and functional remission are achievable therapeutic goals. However, a substantial number of patients show resistance to multiple drugs. In particular, patients whose disease activity cannot be controlled despite the use of two or more biological disease-modifying antirheumatic drugs (DMARDs) or targeted synthetic DMARDs (tsDMARDs) with different mechanisms of action (MOA) have recently been referred to as having difficult-to-treat RA (D2T RA). D2T RA is a heterogeneous and multifactorial disease state, and the major problems are uncontrolled disease activity and decreased quality of life, as well as the economic burden due to frequent healthcare utilization and multiple admissions. Since the concept of D2T RA is relatively new and publication regarding D2T RA is limited, the mechanism underlying DMARD inefficacy and which factors form a &#x201c;difficult-to-treat&#x201d; state in such patients are not yet fully understood. It is also possible that factors contributing to D2T RA may differ by patient, sex, country, and race. The present Mini Review introduces the current concept and unsolved problems of D2T RA, including the definition, prevalence, and factors contributing to D2T RA. We then discuss the management and therapeutic strategies for D2T RA. Finally, we explore a clinical approach to prevent patients from developing D2T RA.

Difficult-to-treat rheumatoid arthritis: Current concept and unsolved problems

Rheumatoid arthritis is an autoimmune disease characterized by chronic symmetric synovial inflammation and erosive bone destruction. Mitochondria are the main site of cellular energy supply and play a key role in the process of energy metabolism. They possess certain self-regulatory and repair capabilities. Mitochondria maintain relative stability in number, morphology, and spatial structure through biological processes, such as biogenesis, fission, fusion, and autophagy, which are collectively called mitochondrial homeostasis. An imbalance in the mitochondrial homeostatic environment will affect immune cell energy metabolism, synovial cell proliferation, apoptosis, and inflammatory signaling. These biological processes are involved in the onset and development of rheumatoid arthritis. In this review, we found that in rheumatoid arthritis, abnormal mitochondrial homeostasis can mediate various immune cell metabolic disorders, and the reprogramming of immune cell metabolism is closely related to their inflammatory activation. In turn, mitochondrial damage and homeostatic imbalance can lead to mtDNA leakage and increased mtROS production. mtDNA and mtROS are active substances mediating multiple inflammatory pathways. Several rheumatoid arthritis therapeutic agents regulate mitochondrial homeostasis and repair mitochondrial damage. Therefore, modulation of mitochondrial homeostasis would be one of the most attractive targets for the treatment of rheumatoid arthritis.

Rheumatoid arthritis is an autoimmune disease characterized by chronic symmetric synovial inflammation and erosive bone destruction. Mitochondria are the main site of cellular energy supply and play a key role in the process of energy metabolism. They possess certain self-regulatory and repair capabilities. Mitochondria maintain relative stability in number, morphology, and spatial structure through biological processes, such as biogenesis, fission, fusion, and autophagy, which are collectively called mitochondrial homeostasis. An imbalance in the mitochondrial homeostatic environment will affect immune cell energy metabolism, synovial cell proliferation, apoptosis, and inflammatory signaling. These biological processes are involved in the onset and development of rheumatoid arthritis. In this review, we found that in rheumatoid arthritis, abnormal mitochondrial homeostasis can mediate various immune cell metabolic disorders, and the reprogramming of immune cell metabolism is closely related to their inflammatory activation. In turn, mitochondrial damage and homeostatic imbalance can lead to mtDNA leakage and increased mtROS production. mtDNA and mtROS are active substances mediating multiple inflammatory pathways. Several rheumatoid arthritis therapeutic agents regulate mitochondrial homeostasis and repair mitochondrial damage. Therefore, modulation of mitochondrial homeostasis would be one of the most attractive targets for the treatment of rheumatoid arthritis.

Rheumatoid arthritis and mitochondrial homeostasis: The crossroads of metabolism and immunity

Rheumatoid arthritis (RA) is an autoimmune disease, in which the inflammatory processes involve the skeletal system and there is marked destruction of the bones and the surrounding structures. In this review, we discuss the current concepts of osteoimmunology in RA, which represent the molecular crosstalk between the immune and skeletal systems, resulting in the disruption of bone remodeling. Bone loss in RA can be focal or generalized, leading to secondary osteoporosis. We have summarized the recent studies of bone loss in RA, which focused on the molecular aspects, such as cytokines, autoantibodies, receptor activator of nuclear kappa-β ligand (RANKL) and osteoprotegerin (OPG). Apart from the above molecules, the role of aryl hydrocarbon receptor (Ahr), which is a potential key mediator in this process through the generation of the Th17 cells, is discussed. Hence, this review highlights the key insights into molecular mechanisms of bone loss in RA.

Rheumatoid arthritis (RA) is an autoimmune disease, in which the inflammatory processes involve the skeletal system and there is marked destruction of the bones and the surrounding structures. In this review, we discuss the current concepts of osteoimmunology in RA, which represent the molecular crosstalk between the immune and skeletal systems, resulting in the disruption of bone remodeling. Bone loss in RA can be focal or generalized, leading to secondary osteoporosis. We have summarized the recent studies of bone loss in RA, which focused on the molecular aspects, such as cytokines, autoantibodies, receptor activator of nuclear kappa-&#x3b2; ligand (RANKL) and osteoprotegerin (OPG). Apart from the above molecules, the role of aryl hydrocarbon receptor (Ahr), which is a potential key mediator in this process through the generation of the Th17 cells, is discussed. Hence, this review highlights the key insights into molecular mechanisms of bone loss in RA.

Pathomechanisms of bone loss in rheumatoid arthritis

The vastly diverse nature of systemic lupus erythematosus (SLE) poses great challenges to clinicians and patients, as well as to research and drug development efforts. Precise management of lupus patients would be advanced by the ability to identify specific abnormalities operative in individual patients at the time of encounter with the clinician. Advances in new technologies and bioinformatics have greatly improved the understanding of the pathophysiology of SLE. Recent research has focused on the discovery and classification of sensitive and specific markers that could aid early accurate diagnosis, better monitoring of disease and identification of appropriate therapy choices based on specific dysregulated molecular pathways. Here, we summarize some of the advances and discuss the challenges in moving toward precise patient-centric management modalities in SLE.

The vastly diverse nature of systemic lupus erythematosus (SLE) poses great challenges to clinicians and patients, as well as to research and drug development efforts. Precise management of lupus patients would be advanced by the ability to identify specific abnormalities operative in individual patients at the time of encounter with the clinician. Advances in new technologies and bioinformatics have greatly improved the understanding of the pathophysiology of SLE. Recent research has focused on the discovery and classification of sensitive and specific markers that could aid early accurate diagnosis, better monitoring of disease and identification of appropriate therapy choices based on specific dysregulated molecular pathways. Here, we summarize some of the advances and discuss the challenges in moving toward precise patient-centric management modalities in SLE.

Current Status of the Evaluation and Management of Lupus Patients and Future Prospects

Frozen shoulder is a common epidemiological affliction. Data acquired from people who suffer from this type of damage in other joints such as the hip, wrist and ankle also exist; although these syndromes are less common. Treatment for frozen shoulder is primarily physical (physiotherapy, manual therapy), secondary medical (corticosteroid injections) and finally surgical but with limited success. The difficulty in treating this type of condition successfully lies in the lack of knowledge about the risk factors involved and the pathophysiology underlying this mysterious syndrome. This review gives an overview of the current scientific position of frozen shoulder in terms of evolutionary factors, etiology, the different mechanisms of action involved, current treatment options and other possible interventions based on recent discoveries of pathophysiological mechanisms. The overall objective is to clarify several unknown aspects of a syndrome that affects up to 5% of the world's population.

Frozen shoulder is a common epidemiological affliction. Data acquired from people who suffer from this type of damage in other joints such as the hip, wrist and ankle also exist; although these syndromes are less common. Treatment for frozen shoulder is primarily physical (physiotherapy, manual therapy), secondary medical (corticosteroid injections) and finally surgical but with limited success. The difficulty in treating this type of condition successfully lies in the lack of knowledge about the risk factors involved and the pathophysiology underlying this mysterious syndrome. This review gives an overview of the current scientific position of frozen shoulder in terms of evolutionary factors, etiology, the different mechanisms of action involved, current treatment options and other possible interventions based on recent discoveries of pathophysiological mechanisms. The overall objective is to clarify several unknown aspects of a syndrome that affects up to 5% of the world&apos;s population.