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Neuroimmunology research and development has been marked by substantial advances, particularly in the treatment of neuroimmunological diseases, such as multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disorders, and myelin oligodendrocyte glycoprotein antibody disease. With more than 20 drugs approved for multiple sclerosis alone, treatment has become more personalised. The approval of disease-modifying therapies, particularly those targeting B cells, has highlighted the role of immunotherapeutic interventions in the management of these diseases. Despite these successes, challenges remain, particularly for patients who do not respond to conventional therapies, underscoring the need for innovative approaches. The approval of monoclonal antibodies, such as ocrelizumab and ofatumumab, which target CD20, and inebilizumab, which targets CD19, for the treatment of various neuroimmunological diseases reflects progress in the understanding and management of B-cell activity. However, the limitations of these therapies in halting disease progression or activity in patients with multiple sclerosis or neuromyelitis optica spectrum disorders have prompted the exploration of cell-based therapies, particularly chimeric antigen receptor (CAR) T cells. Initially successful in the treatment of B cell-derived malignancies, CAR T cells offer a novel therapeutic mechanism by directly targeting and eliminating B cells, potentially overcoming the shortcomings of antibody-mediated B cell depletion. The use of CAR T cells in autoimmune diseases and B cell-driven neuroimmunological diseases shows promise as a targeted and durable option. CAR T cells act autonomously, penetrating deep tissue and effectively depleting B cells, especially in the CNS. Although the therapeutic potential of CAR T cells is substantial, their application faces hurdles such as complex logistics and management of therapy-associated toxic effects. Ongoing and upcoming clinical trials will be crucial in determining the safety, efficacy, and applicability of CAR T cells. As research progresses, CAR T cell therapy has the potential to transform treatment for patients with neuroimmunological diseases. It could offer extended periods of remission and a new standard in the management of autoimmune and neuroimmunological disorders. [ABSTRACT FROM AUTHOR]

Background: Autoinflammatory diseases (AIDs) are rare, mostly genetic diseases that affect the innate immune system and are associated with inflammatory symptoms. Both paediatric and adult patients face daily challenges related to their disease, diagnosis and subsequent treatment. For this reason, a survey was developed in collaboration between the FMF & AID Global Association and the Erlangen Center for Periodic Systemic Autoinflammatory Diseases. Methods: The aim of the survey was to collect the personal assessment of affected patients with regard to their current status in terms of diagnostic timeframes, the interpretation of genetic tests, the number of misdiagnoses, and pain and fatigue despite treatment. Results: In total, data from 1043 AID patients (829 adults and 214 children/adolescents) from 52 countries were collected and analyzed. Familial Mediterranean fever (FMF) (521/50%) and Behçet's disease (311/30%) were the most frequently reported diseases. The average time to diagnosis was 3 years for children/adolescents and 14 years for adults. Prior to the diagnosis of autoinflammatory disease, patients received several misdiagnoses, including psychosomatic disorders. The vast majority of patients reported that genetic testing was available (92%), but only 69% were tested. A total of 217 patients reported that no increase in acute-phase reactants was detected during their disease episodes. The intensity of pain and fatigue was measured in AID patients and found to be high. A total of 88% of respondents received treatment again, while 8% reported no treatment. Conclusions: AID patients, particularly adults, suffer from significant delays in diagnosis, misdiagnosis, and a variety of symptoms, including pain and fatigue. Based on the results presented, raising awareness of these diseases in the wider medical community is crucial to improving patient care and quality of life. [ABSTRACT FROM AUTHOR]

Objectives To evaluate enthesitis treatment response, including time to resolution and data from multiple enthesitis instruments, in patients with PsA treated with secukinumab or adalimumab for 52 weeks. Methods In this post hoc analysis of the EXCEED study, patients receiving secukinumab 300 mg or adalimumab 40 mg per the label were grouped by presence or absence of baseline enthesitis based on the Leeds Enthesitis Index (LEI) and the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC). Efficacy was assessed according to several enthesitis-related instruments using non-responder imputation for the achievement of enthesitis resolution (LEI/SPARCC = 0), Kaplan–Meier analysis for time to resolution, and as-observed data for other outcomes. Results Enthesitis was present at baseline in 498 of 851 patients (58.5%) as assessed by LEI and in 632 of 853 patients (74.1%) as assessed by SPARCC. Patients with baseline enthesitis generally presented with greater disease activity. Similar proportions of patients receiving secukinumab or adalimumab achieved resolution of LEI and SPARCC at weeks 24 (secukinumab: LEI/SPARCC, 49.6%/45.8%; adalimumab: LEI/SPARCC, 43.6%/43.5%) and 52 (secukinumab: LEI/SPARCC, 60.7%/53.2%; adalimumab: LEI/SPARCC, 55.3%/51.4%), with comparable mean time to enthesitis resolution. Improvements were similar for both drugs at individual enthesitis sites. Resolution of enthesitis with secukinumab or adalimumab was associated with improvements in quality of life at week 52. Conclusion Secukinumab and adalimumab showed similar efficacy, including time to resolution, with respect to resolution of enthesitis. Inhibition of IL-17 with secukinumab reduced clinical enthesitis similarly to TNF-α inhibition. Trial registration ClinicalTrials.gov , NCT02745080 [ABSTRACT FROM AUTHOR]

Despite the tremendous progress in the clinical management of autoimmune diseases, many patients do not respond to the currently used treatments. Autoreactive B cells play a key role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B-cell-depleting monoclonal antibodies, such as rituximab, have poor therapeutic efficacy in autoimmune diseases, mainly due to the persistence of autoreactive B cells in lymphatic organs and inflamed tissues. The adoptive transfer of T cells engineered to target tumour cells via chimeric antigen receptors (CARs) has emerged as an effective treatment modality in B-cell malignancies. In the last 2 years treatment with autologous CAR T cells directed against the CD19 antigen has been introduced in therapy of autoimmune disease. CD19 CAR T cells induced a rapid and sustained depletion of circulating B cells, as well as in a complete clinical and serological remission of refractory systemic lupus erythematosus and dermatomyositis. In this paper, we discuss the evolving strategies for targeting autoreactive B cells via CAR T cells, which might be used for targeted therapy in autoimmune diseases. [ABSTRACT FROM AUTHOR]

Introduction: Guselkumab, a novel interleukin-23p19 subunit monoclonal antibody, has been shown to effectively improve the diverse manifestations of active psoriatic arthritis (PsA) in two phase 3 trials (DISCOVER-1, DISCOVER-2). Serum concentrations of extracellular matrix (ECM) biomarkers at baseline and following treatment with guselkumab were evaluated in patients with active PsA, and the relationship of these biomarkers with baseline PsA characteristics and clinical response to guselkumab treatment was explored. Methods: Serum samples were collected at weeks 0, 4, 24, and 52 from a selected subset (N = 260) of the 739 biologic-naïve patients with PsA treated with guselkumab 100 mg every 4 or 8 weeks or placebo in DISCOVER-2. Demographically matched healthy controls (N = 76) were used for comparison. The samples were analyzed for ECM biomarkers associated with collagen degradation (C1M, C2M, C3M, C4M, C6M, C10C) and collagen formation (PRO-C1, PRO-C2, PRO-C3, PRO-C4, PRO-C6). Results: Baseline concentrations of collagen degradation biomarkers C1M, C3M, C4M, and C6M and collagen formation biomarkers PRO-C3 and PRO-C6 were significantly higher (i.e., ≥ 1.25-fold and false discovery rate adjusted p < 0.05) in PsA patients than in healthy controls. Serum C1M, C3M, C4M, and C6M levels declined from baseline in guselkumab-treated patients in both dosing regimens. In addition, guselkumab-treated ACR20 responders (≥ 20% improvement in American College of Rhematology response criteria) had significantly lower C1M levels than ACR20 nonresponders. Conclusion: These data demonstrate that serum collagen biomarkers are elevated in patients with PsA compared with healthy controls and that treatment with guselkumab decreases levels of C1M, C3M, C4M, and C6M. Importantly, C1M serves as a biomarker that associates with improvement of joint signs and symptoms. Trial Registration: ClinicalTrials.gov identifier: NCT03158285. [ABSTRACT FROM AUTHOR]

Psoriatic arthritis (PsA) is part of a group of closely related clinical phenotypes ('psoriatic disease') that is defined by shared molecular pathogenesis resulting in excessive, prolonged inflammation in the various tissues affected, such as the skin, the entheses or the joints. Psoriatic disease comprises a set of specific drivers that promote an aberrant immune response and the consequent development of chronic disease that necessitates therapeutic intervention. These drivers include genetic, biomechanical, metabolic and microbial factors that facilitate a robust and continuous mobilization, trafficking and homing of immune cells into the target tissues. The role of genetic variants involved in the immune response, the contribution of mechanical factors triggering an exaggerated inflammatory response (mechanoinflammation), the impact of adipose tissue and altered lipid metabolism and the influence of intestinal dysbiosis in the disease process are discussed. Furthermore, the role of key cytokines, such as IL-23, IL-17 and TNF, in orchestrating the various phases of the inflammatory disease process and as therapeutic targets in PsA is reviewed. Finally, the nature and the mechanisms of inflammatory tissue responses inherent to PsA are summarized. [ABSTRACT FROM AUTHOR]

Objectives To investigate the dynamics of response of synovitis to IL-17A inhibition with secukinumab in patients with active PsA using Power Doppler ultrasound. Methods The randomized, placebo-controlled, Phase III ULTIMATE study enrolled PsA patients with active ultrasound synovitis and clinical synovitis and enthesitis having an inadequate response to conventional DMARDs and naïve to biologic DMARDs. Patients were randomly assigned to receive either weekly subcutaneous secukinumab (300 or 150 mg according to the severity of psoriasis) or placebo followed by 4-weekly dosing thereafter. The primary outcome was the mean change in the ultrasound Global EULAR and OMERACT Synovitis Score (GLOESS) from baseline to week 12. Key secondary endpoints included ACR 20 and 50 responses. Results Of the 166 patients enrolled, 97% completed 12 weeks of treatment (secukinumab, 99%; placebo, 95%). The primary end point was met, and the adjusted mean change in GLOESS was higher with secukinumab than placebo [−9 (0.9) vs −6 (0.9), difference (95% CI): −3 (−6, −1); one-sided P= 0.004] at week 12. The difference in GLOESS between secukinumab and placebo was significant as early as one week after initiation of treatment. All key secondary endpoints were met. No new or unexpected safety findings were reported. Conclusion This unique ultrasound study shows that apart from improving the signs and symptoms of PsA, IL-17A inhibition with secukinumab leads to a rapid and significant reduction of synovitis in PsA patients. Trial registration ClinicalTrials.gov; NCT02662985. [ABSTRACT FROM AUTHOR]

Objective: We assessed and compared immunologic differences and associations with clinical response to guselkumab, a fully human interleukin (IL)–23p19 subunit inhibitor, in participants with active psoriatic arthritis (PsA) who were biologic‐naive or had inadequate response to tumor necrosis factor inhibitors (TNFi‐IR). Methods: Serum biomarker levels at baseline and after treatment with guselkumab 100 mg every 8 weeks were compared between biologic‐naive (n = 251) and TNFi‐IR (n = 93) subgroups identified in the pooled DISCOVER‐1/DISCOVER‐2/COSMOS data set. Baseline biomarker levels determined by achievement of week 24 clinical responses (≥75%/90% improvement in Psoriasis Area and Severity Index [PASI 75/90], Investigator's Global Assessment [IGA] of psoriasis score 0/1 and ≥2‐point improvement], ≥20% improvement in American College of Rheumatology criteria [ACR20]) were compared between prior treatment subgroups. Results: Baseline IL‐22, TNFα, and beta defensin‐2 (BD‐2) levels were significantly lower in biologic‐naive than in TNFi‐IR participants. With guselkumab, week 24 IL‐17A, IL‐17F, IL‐22, serum amyloid A, C‐reactive protein, IL‐6, and BD‐2 levels were significantly reduced from baseline in biologic‐naive and TNFi‐IR participants (≥1.4‐fold difference, nominal P < 0.05). Clinical responders to guselkumab exhibited significantly higher baseline levels of several biomarkers than nonresponders (IL‐17A, IL‐17F, BD‐2 in biologic‐naive PASI 90 responders; IL‐17A, BD‐2 in TNFi‐IR IGA 0/1 responders; IL‐22, BD‐2 in TNFi‐IR PASI 90 responders [nominal P < 0.05]) and trended higher in TNFi‐IR ACR20 responders. Conclusion: Guselkumab modulates IL‐23 signaling and provides consistent pharmacodynamic effects in both biologic‐naive and TNFi‐IR PsA patients. Significantly elevated baseline IL‐22, TNFα, and BD‐2 levels and associations between baseline IL‐22, IL‐17A, and BD‐2 levels and skin responses to guselkumab suggest greater dysregulation of IL‐23/Th17 signaling in patients with TNFi‐IR. [ABSTRACT FROM AUTHOR]

The article focuses on the challenges and factors contributing to treatment resistance in psoriatic arthritis (PsA), emphasizing the heterogeneity of the disease and the limitations of current therapies. It discusses various aspects such as intrinsic immune escape phenomena, metabolic comorbidities, mental health factors, structural damage, concomitant rheumatologic diseases, sex, socioeconomic factors, and contraindications to treatment.

Cure is the aspirational aim for the treatment of all diseases, including chronic inflammatory conditions such as rheumatoid arthritis (RA); however, it has only been during the twenty-first century that remission, let alone cure, has been a regularly achievable target in RA. Little research has been carried out on how to cure RA, and the term 'cure' still requires definition for this disease. Even now, achieving a cure seems to be a rare occurrence among individuals with RA. Therefore, this Review is aimed at addressing the obstacles to the achievement of cure in RA. The differences between remission and cure in RA are first defined, followed by a discussion of the underlying factors (referred to as drivers) that prevent the achievement of cure in RA by triggering sustained immune activation and effector cytokine production. Such drivers include adaptive immune system activation, mesenchymal tissue priming and so-called 'remote' (non-immune and non-articular) factors. Strategies to target these drivers are also presented, with an emphasis on the development of strategies that could complement currently used cytokine inhibition and thereby improve the likelihood of curing RA. [ABSTRACT FROM AUTHOR]

Enormous progress has been made in the field of rheumatology in the past several decades, historically led by publicly funded academic innovators but in more recent times with much greater involvement of the pharmaceutical industry. This shift in resources has created a complex new model for reinvestment in the medical community in which the vast majority of private funds are redirected towards influencing the prescription behaviour of practitioners through 'key opinion leaders', with the main purpose of enhancing and perpetuating profit rather than innovation and critical thinking, and often at the expense of partnerships with scientists (that is, basic and translational researchers) and academic collaborations. This new episteme brings multiple opportunities to rethink approaches to sustaining long-term critical research in the field, ultimately maximizing the return on investment: scientific knowledge for the benefit of patients and society. Central to such strategies should be the rebalancing of academia-industry partnerships towards academic research and the involvement of 'innovation and knowledge leaders', rather than mostly key opinion leaders. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by severe acute respiratory syndrome coronavirus 2, which predominantly affects the lungs and, under certain circumstances, leads to an excessive or uncontrolled immune activation and cytokine response in alveolar structures. The pattern of pro-inflammatory cytokines induced in COVID-19 has similarities to those targeted in the treatment of rheumatoid arthritis. Several clinical studies are underway that test the effects of inhibiting IL-6, IL-1β or TNF or targeting cytokine signalling via Janus kinase inhibition in the treatment of COVID-19. Despite these similarities, COVID-19 and other zoonotic coronavirus-mediated diseases do not induce clinical arthritis, suggesting that a local inflammatory niche develops in alveolar structures and drives the disease process. COVID-19 constitutes a challenge for patients with inflammatory arthritis for several reasons, in particular, the safety of immune interventions during the pandemic. Preliminary data, however, do not suggest that patients with inflammatory arthritis are at increased risk of COVID-19. [ABSTRACT FROM AUTHOR]

Enthesitis is a key manifestation of PsA and current knowledge supports the concept that it may be among the primary events in the development of this disease, as well as other forms of SpA. Patients with PsA seem to have a different threshold to mechanical stress, which may be genetically determined. Hence patients with psoriatic disease respond pathologically with inflammation after being exposed to physiological mechanical stress. Activation of pro-inflammatory mediators such as IL-17 and TNF-α as well as the influx of innate immune cells are key events in the development of enthesitis in PsA. Chronic entheseal inflammation is accompanied by new bone formation, leading to bony spurs in peripheral (entheseophytes) and axial (syndesmophytes) structures. This article reviews the current knowledge on the mechanisms involved in the development of enthesitis in patients with PsA. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is among the most frequent and severe chronic inflammatory diseases. The disease is characterized by ongoing synovial inflammation, which leads to the destruction of cartilage and bone. In RA, the mechanisms of resolution of inflammation, which are normally intact in the joints, are either suppressed or overruled. Little efforts have been undertaken to understand the mechanisms of resolution of arthritis until recently, when several molecular mechanisms have been identified that determine the chronicity and resolution of inflammation in the joints, respectively. This review describes the key concepts of resolution of arthritis mentioning the key mechanisms involved, such as regulatory macrophages, pro-resolving lipid, fatty acid and cytokine mediators, aggregated neutrophil extracellular trap formation, antibody glycosylation changes, and stromal cell alterations that are involved in determining the decision between chronicity and resolution of arthritis. Each of these mechanisms represents a potential therapeutic approach that allows skewing the balance of the inflammatory processes towards resolution. [ABSTRACT FROM AUTHOR]

Over the past several years, a pathophysiological role for the IL-23-IL-17 pathway in human disease has been defined. A subset of rheumatic diseases, including psoriatic arthritis (PsA) and ankylosing spondylitis (AS), are now acknowledged to be triggered by dysregulated IL-23-IL-17 pathway activation. Genetic evidence links the IL-23-IL-17 pathway to inflammation in these rheumatic diseases, and mechanistic data from mice support a functional role for IL-23-IL-17 pathway activation in the development of enthesitis and in entheseal bone formation. Furthermore, analysis of human tissue samples, as well as data from clinical trials, also supports a role for activation of the IL-23-IL-17 pathway in these diseases. The unique bone phenotype that occurs in PsA and AS is a surprising coexistence of both systemic bone loss and periosteal and entheseal bone formation and is likely to be the result of the actions of IL-23 and/or IL-17 on bone. However, the effects of these cytokines on bone cells are complex, and controversy remains regarding their exact roles in the specific bone microenvironments relevant to PsA and AS. [ABSTRACT FROM AUTHOR]

L'avènement des traitements de fond biologiques (bDMARD) a considérablement amélioré la prise en charge des patients souffrant d'arthrite inflammatoire. Cependant, tous les patients n'obtiennent pas la rémission, la maladie pouvant être résistante, même à l'inhibition d'une seule cytokine par bDMARD. Le ciblage simultané ou séquentiel de plusieurs cytokines peut être envisagé en cas de réponse inadéquate au blocage d'une cytokine unique. En dépit de certaines expériences passées décevantes avec les combinaisons de bDMARD, la meilleure compréhension des mécanismes de l'inflammation et du profil de sécurité des bDMARD permet désormais d'envisager le recours à de nouvelles associations de traitements biologiques. Cette revue aborde le rationnel et les données probantes sur les combinaisons de bDMARD dans la prise en charge de l'arthrite inflammatoire. The advent of biologic disease modifying anti-rheumatic drugs (bDMARDs) has considerably improved patient outcomes in inflammatory arthritis. However, not all patients reach the state of remission as disease can be resistant even to single cytokine inhibition by bDMARDs. Simultaneous or sequential inhibition of multiple cytokines may be considered in situations, where disease control is not adequate under singular inhibition of cytokines. Although there have been some disappointing experiences in the past with combination of bDMARDs, the ongoing improvement of our understanding about inflammatory pathways and the overall better safety understanding of bDMARDs seem to make new biologic treatment combinations possible. This review covers the rationale and current evidence for bDMARDs combination in inflammatory arthritis. [ABSTRACT FROM AUTHOR]

In the Methods section under the heading "Statistical Methods" the text '>= 50 improvement in ACR criteria' should have read '>= 50% improvement in ACR criteria'. In the Results section under the heading 'Collagen Biomarkers and Baseline Clinical Features in PsA Patients' the text "PSA" should have read "PsA". [Extracted from the article]

IL-6 is a pleiotropic cytokine involved in many biological functions that affect tissues beyond the immune system and the vasculature. This multifunctional cytokine exerts its actions via the classic signalling pathway when it binds to the transmembrane IL-6 receptor (IL-6R) or via the trans-signalling pathway upon binding to the soluble form of IL-6R (sIL-6R). In general, classic IL-6 signalling is responsible for the anti-inflammatory properties of IL-6, whereas trans-signalling is responsible for the pro-inflammatory actions of IL-6. As a result, dysregulation of the IL-6 axis can lead to the onset or development of several disease states, particularly autoimmune and inflammatory disorders, including RA and GCA. This pathological role of IL-6 means that pharmacologic modulation of the IL-6 axis is a rational therapeutic approach; however, multiple predictable, but often underappreciated, effects on tissues and organs beyond the blood vessels may also occur. [ABSTRACT FROM AUTHOR]

Paraneoplastic syndromes are rare but can have enormous clinical impact on diagnosis and outcome of neoplastic diseases. The rheumatologist should be familiar with a few typical musculoskeletal manifestations of malignancies to be able to diagnose them early for a timely initiation of anti-tumour therapies. This review describes the characteristic features of various paraneoplastic arthritides and vasculitides, cancer-associated myositis, hypertrophic osteoarthropathy, and tumour-induced osteomalacia. In addition, the current knowledge about underlying pathomechanisms of these syndromes is discussed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is a chronic autoimmune disease that causes progressive articular damage, functional loss, and comorbidity. The development of effective biologics and small-molecule kinase inhibitors in the past two decades has substantially improved clinical outcomes. Just as understanding of pathogenesis has led in large part to the development of drugs, so have mode-of-action studies of these specific immune-targeted agents revealed which immune pathways drive articular inflammation and related comorbidities. Cytokine inhibitors have definitively proven a critical role for tumour necrosis factor α and interleukin 6 in disease pathogenesis and possibly also for granulocyte-macrophage colony-stimulating factor. More recently, clinical trials with Janus kinase (JAK) inhibitors have shown that cytokine receptors that signal through the JAK/STAT signalling pathway are important for disease, informing the pathogenetic function of additional cytokines (such as the interferons). Finally, successful use of costimulatory blockade and B-cell depletion in the clinic has revealed that the adaptive immune response and the downstream events initiated by these cells participate directly in synovial inflammation. Taken together, it becomes apparent that understanding the effects of specific immune interventions can elucidate definitive molecular or cellular nodes that are essential to maintain complex inflammatory networks that subserve diseases like rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Structural damage of cartilage and bone tissue is a hallmark of rheumatoid arthritis (RA). The resulting joint destruction constitutes one of the major disease consequences for patients and creates a significant burden for the society. The main cells executing bone and cartilage degradation are osteoclasts and fibroblast-like synoviocytes, respectively. The function of both cell types is heavily influenced by the immune system. In the last decades, research has identified several mediators of structural damage, ranging from infiltrating immune cells and inflammatory cytokines to autoantibodies. These factors result in an inflammatory milieu in the affected joints which leads to an increased development and function of osteoclasts and the transformation of fibroblast-like synoviocytes towards a highly migratory and destructive phenotype. In addition, repair mechanisms mediated by osteoblasts and chondrocytes are strongly impaired by the presence of pro-inflammatory cytokines. This article will review the current knowledge on the mechanisms of joint inflammation and the destruction of bone and cartilage. [ABSTRACT FROM AUTHOR]

Bone loss is a central feature of rheumatoid arthritis (RA). It is considered to represent a sign of irreversible structural damage triggered by chronic inflammation. Recent evidence, however, suggests that autoantibodies are an important and earlier driver for bone damage in RA. This article summarizes current evidence for the role of RA-related autoantibodies in mediating bone loss. Rheumatoid factor and antibodies recognizing modified (citrullinated) proteins are the central features of autoimmunity in RA patients. Despite being used as diagnostic markers for many years, ascertaining the differentiation of RA from other forms of inflammatory arthritides, the role of these antibodies as pathogenic players has long been unrecognized. Recently, several pieces of evidence suggested that bone-resorbing osteoclasts are highly responsive to RA-related autoantibodies, providing a novel link between autoimmunity and bone. These developments have allowed unraveling the underlying mechanisms, which are responsible for the well-known clinical observation that RA-related autoantibodies are associated with a more severe disease course. At present, rheumatoid factor and antibodies recognizing citrullinated proteins are considered as potent osteoclast inducers and triggers for bone loss in arthritis. [ABSTRACT FROM AUTHOR]

The myeloid cell-derived cytokine interleukin (IL-23) has been identified as an orchestrator of chronic inflammatory disease. IL-23 is instrumental in the activation of effector T cells and innate lymphoid cells, which in turn allow the mobilization of pro-inflammatory macrophages and neutrophils from the bone marrow and the initiation of inflammation in the joints, the gut and the skin. While the role of IL-23 in mounting chronic skin inflammation in the context of psoriasis is well established, increasing evidence suggests that also colitis and psoriatic arthritis are controlled by IL-23. Psoriasis, Crohn's disease and psoriatic arthritis share a common genetic link to IL-23 receptor haplotypes and a therapeutic response to neutralization of IL-23. By controlling the expression of downstream effector cytokines IL-17A and TNFa, IL-23 triggers entheseal and synovial inflammation in patients with psoriatic arthritis by activating T cells and permitting the influx of macrophages and neutrophils into entheses and joints. Furthermore, IL-23 also influences structural changes in the joints of patients with psoriatic arthritis by enhancing osteoclast mediated bone resorption leading to bone erosion, as well as by modulating bone-forming osteoblasts resulting in bony spur formation and ankylosis. In summary, IL-23 represents a highly specialized inflammatory mediator, which is involved in the communication of inflammation across organs. IL-23 is positioned at the initiation point of a pro-inflammatory cytokine cascade that precipitates the development of psoriatic arthritis. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-1, first described ∼35 years ago as a secreted product of monocytes and neutrophils, refers to IL-1α and IL-1β, two key cytokines in the activation of innate immunity. These cytokines were among the first proteins identified as orchestrators of leukocyte communication, creating the class of secreted products now known as interleukins. The IL-1 family comprises a total of 11 members, including the two activating cytokines IL-1α and IL-1β as well as an inhibitory mediator, the IL-1 receptor antagonist. IL-1 is processed and activated by a caspase-1 dependent mechanism in conjunction with inflammasome assembly, as well as by caspase-1 independent processes that involve neutrophil proteases. Once activated, IL-1α and IL-1β act as potent proinflammatory cytokines at the local level, triggering vasodilatation and attracting monocytes and neutrophils to sites of tissue damage and stress. Importantly, these cytokines are crucial for the induction of matrix enzymes and serve as potent mediators of tissue damage by altering cartilage and bone homeostasis. Systemically, IL-1 cytokines foster the hypothalamic fever response and promote hyperalgesia. Uncontrolled IL-1 activation is a central component of some inflammatory diseases, including rare hereditary syndromes with mutations in inflammasome-associated genes or more frequent diseases such as gout, characterized by neutrophil infiltration and IL-1 activation. Apart from these connections to inflammatory diseases, an important role for IL-1 in inflammatory atherogenesis is also predicted. To date, four potent inhibitors of IL-1 are available for clinical use or in late-stage clinical development, which not only constitute efficacious therapies, but also helped improve our understanding of the role of IL-1 in human disease. [ABSTRACT FROM AUTHOR]

For patients that present with musculoskeletal symptoms, diagnostic procedures carried out by physicians and rheumatologists are primarily aimed at confirming or excluding the occurrence of primary rheumatic diseases. Another important trigger for musculoskeletal disease, however, is the presence of a tumour. Careful clinical investigation and knowledge of the gestalt of musculoskeletal syndromes related to respective tumour entities is of utmost importance for the diagnosis of paraneoplastic rheumatic diseases such as hypertrophic osteoarthropathy, paraneoplastic polyarthritis, RS3PE syndrome, palmar fasciitis and polyarthritis, cancer-associated myositis and tumour-induced osteomalacia. This places great responsibility on rheumatologists in diagnosing malignancies and referring the patient for effective treatment. The selective influence of tumours on musculoskeletal tissue is surprising and indicates that tumours alter tissues such as the periosteum, synovial membrane, subcutaneous connective t issue, fascia, muscles and bones by specific molecular processes. Some of the underlying mechanisms have been unravelled, providing valuable information on the physiologic and pathophysiologic roles of mediators such as vascular endothelial growth factor and fibroblast growth factor 23. [ABSTRACT FROM AUTHOR]

The article focuses on the contrasting outcomes of CAR T-cell therapy in patients with systemic lupus erythematosus (SLE) and systemic sclerosis, highlighting prompt clinical and serologic remission in SLE patients but less complete remission in systemic sclerosis patients, suggesting that CAR T-cell therapy efficacy may vary based on autoimmune condition and emphasizing the need for tailored approaches rather than a universal solution.

Anaemia is frequently observed in patients with inflammatory rheumatic diseases. Depending on its severity, anaemia negatively affects cardiovascular performance, physical activity and the quality of life of patients. However, anaemia is considered to be a symptom of the underlying inflammatory disease and, thus, neglected as a complex medical condition that warrants specific diagnosis and treatment. Although inflammation-induced alterations in iron homeostasis and erythropoiesis have a dominant role in the pathogenesis of this type of anaemia, multiple other factors such as chronic blood loss, haemolysis, disease and treatment-associated adverse effects or vitamin deficiencies can also take part in the development of anaemia. Accordingly, the prevalence of anaemia is positively associated with the severity of the underlying disease. This Review will summarize epidemiological data on anaemia in inflammatory rheumatic diseases, along with a detailed description of underlying pathophysiological pathways, available diagnostic tools and practical diagnostic strategies. Discussion of established and newly emerging treatment regimens, as well as the need for further research in this clinically relevant field, will also be included. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To evaluate if type 2 diabetes is an independent risk predictor for severe osteoarthritis (OA). RESEARCH DESIGN AND METHODS--Population-based cohort study with an age- and sex-stratified random sample of 927 men and women aged 40-80 years and followed over 20 years (1990-2010). RESULTS--Rates of arthroplasty (95% CI) were 17.7 (9.4-30.2) per 1,000 person-years in patients with type 2 diabetes and 5.3 (4.1-6.6) per 1,000 person-years in those without (P <0.001). Type 2 diabetes emerged as an independent risk predictor for arthroplasty: hazard ratios (95%CI), 3.8 (2.1-6.8) (P<0.001) in an unadjusted analysis and 2.1 (1.1-3.8) (P = 0.023) after adjustment for age, BMI, and other risk factors for OA. The probability of arthroplasty increased with disease duration of type 2 diabetes and applied to men and women, as well as subgroups according to age and BMI. Our findings were corroborated in cross-sectional evaluation by more severe clinical symptoms of OA and structural joint changes in subjects with type 2 diabetes compared with those without type 2 diabetes. CONCLUSIONS--Type 2 diabetes predicts the development of severe OA independent of age and BMI. Our findings strengthen the concept of a strong metabolic component in the pathogenesis of OA. [ABSTRACT FROM AUTHOR]

Bone erosion is a central feature of rheumatoid arthritis and is associated with disease severity and poor functional outcome. Erosion of periarticular cortical bone, the typical feature observed on plain radiographs in patients with rheumatoid arthritis, results from excessive local bone resorption and inadequate bone formation. The main triggers of articular bone erosion are synovitis, including the production of proinflammatory cytokines and receptor activator of nuclear factor KB ligand (RANKL), as well as antibodies directed against citrullinated proteins. Indeed, both cytokines and autoantibodies stimulate the differentiation of bone-resorbing osteoclasts, thereby stimulating local bone resorption. Although current antirheumatic therapy inhibits both bone erosion and inflammation, repair of existing bone lesions, albeit physiologically feasible, occurs rarely. Lack of repair is due, at least in part, to active suppression of bone formation by proinflammatory cytokines. This Review summarizes the substantial progress that has been made in understanding the pathophysiology of bone erosions and discusses the improvements in the diagnosis, monitoring and treatment of such lesions. [ABSTRACT FROM AUTHOR]

Objective To evaluate the efficacy and safety of apremilast, a novel, orally available small molecule that specifically targets phosphodiesterase 4, in the treatment of active psoriatic arthritis (PsA). Methods This phase II, multicenter, randomized, double-blind, placebo-controlled study included the following: a 12-week treatment phase, with patients receiving placebo, apremilast 20 mg twice per day, or apremilast 40 mg once per day; a 12-week treatment-extension phase, with patients in the placebo group re-randomized to receive apremilast; and a 4-week observational phase after treatment cessation. The primary end point was the proportion of patients achieving the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Safety assessments included adverse events (AEs), physical examinations, vital signs, laboratory parameters, and electrocardiograms. Results Of the 204 patients with PsA who were randomized to a treatment group, 165 completed the treatment phase. At the end of the treatment phase (week 12), 43.5% of patients receiving apremilast 20 mg twice per day ( P < 0.001) and 35.8% of those receiving 40 mg once per day ( P = 0.002) achieved an ACR20 response, compared with 11.8% of those receiving placebo. At the end of the treatment-extension phase (week 24), >40% of patients in each group (patients receiving apremilast 20 mg twice per day, patients receiving apremilast 40 mg once per day, and patients in the placebo group re-randomized to receive apremilast) achieved the ACR20 level of improvement. Most patients in the treatment phase (84.3%) and treatment-extension phase (68.3%) reported ≥1 AE. Diarrhea, headache, nausea, fatigue, and nasopharyngitis were reported most frequently; most events were mild or moderate. No clinically relevant laboratory or electrocardiographic abnormalities were reported. Conclusion Treatment with apremilast at a dosage of 20 mg twice per day or 40 mg once per day demonstrated efficacy in comparison with placebo and was generally well tolerated in patients with active PsA. The balance of efficacy, tolerability, and safety supports further study of apremilast in PsA. [ABSTRACT FROM AUTHOR]

The article describes the pathogenesis of rheumatoid arthritis, a common autoimmune disease with no known cause that is associated with progressive disability, systemic complications, early death and socioeconomic costs. It discusses the study findings implicating genetic factors and gene-environment interactions in rheumatoid arthritis. It discusses why cytokine production is central to the pathogenesis of the disease. The structural damage and systemic consequences of the disease are tackled.

Eur J Clin Invest 2011; 41 (12): 1361-1366 Abstract Background Inflammatory diseases are linked to enhanced bone loss. The effect of inflammation on bone is mediated by proinflammatory cytokines, which regulate bone formation as well as bone resorption thereby altering bone homeostasis. Materials and methods In this article we summarize the key insights in cytokine regulation of bone. We describe the major pro- and anti-inflammatory mediators, which are involved in the regulation of bone and describe the mechanisms by which these cytokines alter bone balance. Results We describe the effects of tumor necrosis factor (TNF), interleukin (IL)- 1 family members, IL-6, IL-17 and interferons (IFN) on bone and discuss the mechanisms by which these individual cytokines affect the bone resorbing and the bone forming cells. Conclusions Several proinflammatory cytokines (such as TNFa, IL-1 and IL-17) are major triggers for osteoclast activation explaining the enhanced bone loss during inflammation. Other such as IL-12, IL-18, IL-33 and IFN are strong suppressors of osteoclast differentiation and inhibit bone loss. Thus the cytokine composition of an inflammatory tissue is decisive whether inflammation triggers bone loss or not. [ABSTRACT FROM AUTHOR]

Inflammation perturbs normal bone homeostasis and is known to induce bone loss, as it promotes both local cartilage degradation and local and systemic bone destruction by osteoclasts, as well as inhibits bone formation by osteoblasts. Thus, not surprisingly, inflammatory autoimmune diseases often lead to local and/or general bone loss. However, the mechanisms that target the bone in autoimmune disease are complex and diverse, as they range from a direct attack on the bone and cartilage by the immune cells to indirect consequences of disturbances of the systemic control of bone remodeling. This Review discusses current understanding of the mechanisms of autoimmune-mediated bone loss in view of new insight from two new fields of research: osteoimmunology, which analyzes the direct effect of immune cells on bone, and the integrative metabolism approach, which established the existence of neuroendocrine loops that regulate bone remodeling. [ABSTRACT FROM AUTHOR]

The article offers information on the different animal modes for systemic sclerosis (SSc). Such animal models include mouse model of bleomycin-induced dermal fibrosis, chronic sclerodermatous graft-versus-host disease (GVHD) model, and Fra-2-transgenic mice, among others. The characteristics, advantages and limitations of each animal model are described. In addition, the article offers ideas on how to select the right animal model for research.

The article explores the kinetics of bony spur formation and the association of bony spur formation to synovial inflammation and bone erosion in rat arthritis models. It investigates whether bony spur formation relies on the expression of tumor necrosis factor α (TNFα) or RANKL. The article notes the analysis of the growth of bony spurs in rat collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA).

The article discusses a study to determine other predictors of osteoarthritis (OA) aside from age and overweight. It mentions the methods used such as the assessment of the demographic characteristics and lifestyle, biochemical variables including the level of soluble vascular cell adhesion molecule 1 (VCAM-1), and a record of Bruneck cohort study of severe OA surgery. The result shows that the level of soluble VCAM-1 is a strong and independent predictor for a surgery of severe OA.

A bone marrow edema pattern on MRI has a similar signal quality as an inflamed synovium and may, in fact, reflect true inflammatory infiltrates rather than a pure accumulation of extracellular fluid. Bone lesions near sites of rheumatoid arthritis–related inflammation are heavily vascularized, contributing to the high water content and enhanced visibility on MRI. However, even without erosive change, periarticular bone marrow lesions may be seen. This chapter describes the nature of bone marrow lesions detected by MRI in patients with inflammatory arthritis. [ABSTRACT FROM AUTHOR]

Vitamin K and Vitamin K-dependent proteins (VKDPs) are best known for their pivotal role in blood coagulation. Of the 14 VKPDs identified in humans to date, 6 play also important roles in skeletal biology and disease. Thus, osteocalcin, also termed bone Gla-protein, is the most abundant non-collagenous protein in bone. Matrix Gla protein and Ucma/GRP on the other hand are highly abundant in cartilage. Furthermore, periostin, protein S, and growth arrest specific 6 protein (GAS 6) are expressed in skeletal tissues. The roles for these VKDPs are diverse but include the control of calcification and turnover of bone and cartilage. Vitamin K plays an important role in osteoporosis and serum osteocalcin levels are recognized as a promising marker for osteoporosis. On the other hand, matrix Gla protein and Ucma/GRP are associated with osteoarthritis. This review focuses on the roles of these three VKDPs, osteocalcin, matrix Gla protein and Ucma/GRP, in skeletal development and disease but will also summarize the roles the other skeletal VKDPs (periostin, protein S and GAS6) in skeletal biology. [ABSTRACT FROM AUTHOR]

Wnt proteins regulate organ development, tumorigenesis and bone homeostasis, among other functions. The binding of Wnt proteins to plasma membrane receptors on mesenchymal cells induces the differentiation of these cells into the osteoblast lineage and thereby supports bone formation. Wnts are also key signaling proteins in joint remodeling processes. Active Wnt signaling contributes to osteophyte formation and might have an essential role in the anabolic pattern of joint remodeling that is observed in ankylosing spondylitis and osteoarthritis. By contrast, blockade of Wnt signaling facilitates bone erosion and contributes to catabolic joint remodeling, a process that is observed in rheumatoid arthritis. This Review summarizes current knowledge of the molecular regulation of joint remodeling associated with chronic arthritis, focusing on the role of the Wnt proteins and their inhibitors. It also addresses the role of Wnt in determining the differences in clinical presentation of inflammatory arthropathies and discusses implications for future therapy. [ABSTRACT FROM AUTHOR]

This article discusses the role of tumor necrosis factor α (TNF α) in fibrotic diseases. It references clinical trials that demonstrated the efficacy of TNF α antagonists in diseases such as rheumatoid arthritis (RA) and Chrohn's disease. It explores the effects of effects of TNF α on collagen production and extracellular matrix (ECM) turnover. It shows the effect of TNF α on animal models of congestive heart failure.

Cytokine expression in the inflamed synovial membrane of patients with rheumatoid arthritis and other forms of chronic inflammatory arthritis and other forms of chronic inflammatory arthritis leads to formation of osteoclasts. These cells are primarily involved in the resorption of mineralized cartilage and bone and thus participate in joint damage in the course of chronic arthritides. Osteoclastogenesis in the synovial membrane is driven by cytokines such as RANKL, MCSF but also classical proinflammatory mediators such as TNF, IL-1 and IL-6. Inhibition of osteoclast formation has proven as an effective approach to inhibit structural damage in experimental arthritis and preliminary data suggest that such approaches are also effective in human RA. [ABSTRACT FROM AUTHOR]

Cytokines regulate a broad range of inflammatory processes that are implicated in the pathogenesis of rheumatoid arthritis. In rheumatoid joints, it is well known that an imbalance between pro- and anti-inflammatory cytokine activities favours the induction of autoimmunity, chronic inflammation and thereby joint damage. However, it remains less clear how cytokines are organized within a hierarchical regulatory network, and therefore which cytokines may be the best targets for clinical intervention a priori. Here, we discuss the crucial effector function of cytokines in the immunological processes that are central to the pathogenesis of rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Inflammatory joint disease typically provokes progressive cartilage damage. The proliferative synovial inflammatory tissue directly invades the cartilage and induces the expression and activation of degrading enzymes such as matrix metalloproteases (MMPs) and aggrecanases. However, also chondrocyte apoptosis has been observed in cartilage samples of inflamed joints. It remains unclear whether this is a secondary phenomenon due to cartilage damage or a primary event initiated by the synovial inflammation. To determine the presence or absence of chondrocyte death in experimental arthritis, we longitudinally assessed proteoglycan depletion and chondrocyte apoptosis in paw sections from human tumor necrosis factor transgenic (hTNFtg) mice and wild-type littermates. Whereas, wild-type mice showed no signs of cartilage damage, hTNFtg mice exhibited progressive proteoglycan loss starting at clinical onset of arthritis. However, we already found the first apoptotic chondrocytes well before cartilage matrix breakdown occurred indicating that chondrocyte death can be induced before matrix resorption. Chondrocyte death could constantly be observed until late stages of arthritis causing a continuous increase in the number of empty cartilage lacunae. As apoptotic cells in cartilage cannot be cleared by phagocytes due to their spatial isolation in the avascular lacunae of cartilage, having no contact to professional or amateur phagocytes. The dying cells are compelled to undergo a "lonely death" inevitable ending up in secondary necrosis giving rise to perpetuation of a pro-inflammatory cascade. These data indicate that chondrocyte death may play a primary role in inflammatory arthritis fuelling cartilage inflammation and damage due to secondary necrosis. [ABSTRACT FROM AUTHOR]

The article focuses on the high-sensitivity c-reactive protein (hs-CRP) and risk of non-traumatic fractures in the Bruneck study. The hs-CRP level is a significant and independent risk predictor of non-traumatic fracture. The result is consistent with the hypothesis of a tight interplay between low-grade inflammation and bone turnover.

Abstract: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by antibodies to DNA (anti-DNA). Although these antibodies have features of antigen drive, the source of this DNA is not defined. To assess the potential role of foreign and self-DNA as driving antigens, the specificity of SLE sera for bacterial and mammalian DNA was evaluated. Micrococcus lysodeikticus (MC) and calf thymus (CT) DNA were tested as antigens, with absorption on CT DNA columns used to identify antibodies to antigenic sites on the two DNA. Among 9 sets of longitudinal sera tested, all showed binding to both DNA, and none showed exclusive or predominant binding to CT DNA. With absorbed sera, antibodies could be distinguished in terms of cross-reactive or selective binding to the DNAs. These findings suggest that anti-DNA antibodies vary in specificity and are consistent with a role of both foreign and self-DNA in anti-DNA induction. [Copyright &y& Elsevier]