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1.
Nowadays B and T-cell directed biologics in addition to TNF inhibitors are established as effective and safe treatment options for rheumatoid arthritis. As shown by the approval of rituximab for the treatment of systemic vasculitis, these drugs can also be useful for the treatment of other systemic autoimmune diseases; however, to optimize therapeutic strategies, predictive factors for treatment response as well as a good characterized safety profile are essential. So far implementation of real personalized medicine is not feasible in the field of rheumatology, but first biomarkers have already been identified and provide promising results. In this context, it has been shown that a B-cell directed therapy with rituximab is more effective in seropositive patients with rheumatoid arthritis. In addition, characterization of the cytokine milieu as well as of circulating and tissue infiltrating B and T-cell subsets might be useful for prediction of treatment response in the near future.  相似文献   

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Signal transduction in rheumatoid arthritis   总被引:5,自引:0,他引:5  
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4.
Animal models have played a critical role in the history of modern drug development for rheumatoid arthritis (RA). In this chapter I examine the contributions of animal models in arthritis therapy from adjuvant arthritis and COX-1 inhibitors to transgenic mice and biological response modifiers. Advances in knowledge of the mechanisms of connective tissue disease are frequently derived from the study of animal models, and these findings frequently identify therapeutic targets that are subsequently evaluated in animal models. Hence a critical relationship between insights into the pathology of arthritis and the development of novel therapeutic approaches exists around the study of animal models of arthritis. In particular, we examine how the study of collagen-induced arthritis in rodents led to pioneering work in cytokine inhibitors for the successful therapy of RA.  相似文献   

5.
Tumour necrosis factor‐α is a pleiotropic cytokine which has a broad range of actions in inflammation, infection and immunity. TNF‐α is supposed to play a crucial role in the pathogenesis of various autoimmune diseases. TNF‐α blocking agents have been demonstrated to be highly effective in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis. TNF‐α inhibitors also have been tried with other rheumatic diseases and have emerged as promising treatments. We here review the current evidences of effectiveness of the anti‐TNF‐α therapy in various autoimmune diseases.  相似文献   

6.
INTRODUCTION: Tumor necrosis factor (TNF) blocking agents have changed the therapeutic approach in rheumatoid arthritis, but a true clinical remission remains rare. Gene therapy opens new perspectives in immunotherapy in rheumatoid arthritis. This review focuses on the research, data and clinical development in rheumatoid arthritis using this strategy. CURRENT KNOWLEDGE AND KEY POINTS: New therapeutical targets have been described besides the cytokine inhibitors: apoptosis inducers, angiogenesis inhibitors and metalloprotease inhibitors, cell activation and signalization have been used in experimental models to inhibit arthritis. Gene therapy makes it possible to better understand the physiopathology of rheumatoid arthritis and offers the opportunity to induce true remissions of experimental arthritis. FUTURE PROSPECTS AND PROJECTS: Biotechnology allows the development of new safer vectors which permit long-term expression. However, the difficulties to produce high titers and safe vectors limit the use of this strategy. The previous clinical data on gene therapy in rheumatoid arthritis are limited to feasibility studies. We believe that the efficiency of gene therapy will be obtained by combining two or more complementary targets.  相似文献   

7.
Divergent T-cell cytokine patterns in inflammatory arthritis.   总被引:18,自引:0,他引:18       下载免费PDF全文
A major immunoregulatory mechanism in inflammatory infections and allergic diseases is the control of the balance of cytokines secreted by Th1/Th2 subsets of T helper (Th) cells. This might also be true in autoimmune diseases; a Th2 pattern that prevents an effective immune response in infections with intracellular bacteria may favor immunosuppression in autoimmune disease. The pattern of cytokine expression was compared in the synovial tissue from patients with a typical autoimmune disease, rheumatoid arthritis, and with a disorder with similar synovial pathology but driven by persisting exogenous antigen, reactive arthritis. We screened 12 rheumatoid and 9 reactive arthritis synovial tissues by PCR and in situ hybridization for their expression of T-cell cytokines. The cytokine pattern differs significantly between the two diseases; rheumatoid arthritis samples express a Th1-like pattern whereas in reactive arthritis interferon gamma expression is accompanied by that of interleukin 4. Studying the expression of cytokines by in situ hybridization confirmed the results found by PCR; they also show an extremely low frequency of cytokine-transcribing cells. In a double-staining experiment, it was demonstrated that interleukin 4 is made by CD4 cells. These experiments favor the possibility of therapeutic intervention in inflammatory rheumatic disease by means of inhibitory cytokines.  相似文献   

8.
Interleukin-1 (IL-1) is a primary cytokine that is involved in the pathogenesis of rheumatoid arthritis; it contributes to inflammation and joint destruction. Anakinra (Kineret) is an IL-1 receptor antagonist that blocks the biologic activity of IL-1. It was approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis in 2001. Anakinra is safe and effective in the treatment of rheumatoid arthritis, both as monotherapy and in combination with other disease-modifying antirheumatic drugs.This article reviews the preclinical, clinical, and postmarketing data on the safety and efficacy of anakinra in the treatment of rheumatoid arthritis and focuses on the pivotal clinical trials that led to FDA approval.  相似文献   

9.
Even though rheumatoid arthritis is by definition an inflammatory disease, the complex picture of rheumatoid arthritis really owes its development to three completely different pathogenetic mechanisms, namely: Exudative-proliferative processes in the synovial tissue of joints and tendon sheaths and at serous skins; Destruction of articular cartilage and juxta-articular bone by the aggression of non-inflammatory tumor-like cell elements of synovial origin; Primary, non-inflammatory tissue necroses due to infiltration of immune complexes and complement. It is therefore understandable that all therapeutic approaches which have an antiphlogistic character can only influence pain, swelling and morning stiffness, but not the destruction of the joints and the primarily necrotising processes, which can also destroy vital structures in the heart and vessels.  相似文献   

10.
PURPOSE OF REVIEW: Macrophages differentiate from peripheral-blood monocytes. Both monocytes and synovial macrophages are key players in rheumatoid arthritis. These cells are involved in the initiation and perpetuation of inflammation, leukocyte adhesion and migration, matrix degradation and angiogenesis. Macrophages express adhesion molecules, chemokine receptors and other surface antigens. They also secrete a number of chemokines, cytokines, growth factors, proteases and other mediators. RECENT FINDINGS: Macrophage migration-inhibitory factor has drawn significant attention recently. This cytokine is involved in macrophage activation and cytokine production. Migration-inhibitory factor also regulates glucocorticoid sensitivity and may be a pathogenic link between rheumatoid arthritis and atherosclerosis. Novel macrophage-derived chemokines and chemokine receptors have been identified. Interleukin-10 may have several proinflammatory effects that may influence its action in rheumatoid arthritis. Several proteinases including cathepsin G are produced by macrophages during rheumatoid arthritis-associated inflammatory and angiogenic events. Antirheumatic drugs, imatinib, chemokine receptor inhibitors and other specific strategies may become included in the therapy of rheumatoid arthritis. SUMMARY: Macrophages and their products are key players in the pathogenesis of rheumatoid arthritis and may be good therapeutic targets.  相似文献   

11.
Chronic arthritis is characterized by persistent joint inflammation and concomitant joint destruction. Animal models have been of great value in understanding potential pathogenetic pathways and studying therapeutic principles. The first models were based on T cell-driven pathways and taught us that arthritis can be induced by a variety of stimuli. This suggests that the involvement of a single (auto)antigen in rheumatoid arthritis is unlikely and suggests that the regulation of arthritis can best be approached via bystander suppression. Insight into the pivotal role of TNF alpha and IL-1 has emerged from studies employing a range of common and also novel transgenic models. Combination treatment with both TNF and IL-1 blockers is warranted to control both joint inflammation and joint destruction. Novel approaches with viral gene constructs of cytokines and cytokine inhibitors teach us that efficient gene therapy is a possibility for small joints.  相似文献   

12.
BACKGROUND: The synovial tissue is a primary target of many inflammatory arthropathies, including psoriatic arthritis (PsA). Identification of proinflammatory molecules in the synovium may help to identify potentially therapeutic targets. OBJECTIVE: To investigate extensively the features of cell infiltration and expression of mediators of inflammation and joint destruction in the synovium of patients with PsA compared with patients with rheumatoid arthritis matched for disease duration and use of drugs. METHODS: Multiple synovial tissue biopsy specimens were obtained by arthroscopy from an inflamed joint in 19 patients with PsA (eight oligoarthritis, 11 polyarthritis) and 24 patients with rheumatoid arthritis. Biopsy specimens were analysed by immunohistochemistry to detect T cells, plasma cells, fibroblast-like synoviocytes, macrophages, proinflammatory cytokines, matrix metalloproteinases and tissue inhibitor metalloproteinase-1, adhesion molecules and vascular markers. Stained sections were evaluated by digital image analysis. RESULTS: The synovial infiltrate of patients with PsA and rheumatoid arthritis was comparable with regard to numbers of fibroblast-like synoviocytes and macrophages. T cell numbers were considerably lower in the synovium of patients with PsA. The number of plasma cells also tended to be lower in PsA. The expression of tumour necrosis factor alpha (TNFalpha), interleukin (IL) 1beta, IL6 and IL18 was as high in PsA as in rheumatoid arthritis. The expression of matrix metalloproteinases, adhesion molecules and vascular markers was comparable for PsA and rheumatoid arthritis. CONCLUSION: These data show increased proinflammatory cytokine expression in PsA synovium, comparable to results obtained for rheumatoid arthritis, and support the notion that, in addition to TNFalpha blockade, there may be a rationale for treatments directed at IL1beta, IL6 and IL18.  相似文献   

13.
Tumour necrosis factor‐inhibitor (TNF‐inhibitor) therapy is increasingly used for the treatment of rheumatoid arthritis. While it is effective for the articular manifestations of rheumatoid arthritis we have reason to believe that it is less effective for extra‐articular disease. We present two cases of life‐threatening cardiac tamponade in two patients with well‐controlled rheumatoid arthritis on adalimumab. An extensive literature search was carried out and three other patients were found. We believe that these cases highlight the need for rheumatologists to be vigilant for extra‐articular manifestations of rheumatoid arthritis even in the presence of quiescent joint disease while on TNF‐inhibitors.  相似文献   

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Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX) -2 inhibitors with the potential to reduce the risk of gastrointestinal bleeding, have their crucial role in the control of inflammation. However, they have recently been shown to have a preventing effect against joint destruction by basic studies related to pathophysiology in rheumatoid arthritis. Here we summarize the current knowledge on anti-proliferative action due to apoptosis, suppression of angiogenesis, and suppression of osteoclastic bone resorption by NSAIDs. COX-2-dependent and/or -independent mechanisms for these actions have been suggested. Several NSAIDs including selective COX-2 inhibitors have been suggested to possess the in vivo preventing effects on joint destruction in animal models of rheumatoid arthritis. However, clinical evidence on the disease modifying effects of COX-2 inhibitors in patients with rheumatoid arthritis remains to be studied.  相似文献   

16.
Rationale:Several diseases feature tumors, or tumor-mimicking lesions, that further invade the bone and surrounding joints of the wrist region. Here, we describe 3 rare cases of multiple destructed carpal bones and adjacent joints in different disease entities confirmed via pathologic diagnosis.Patient concerns:All 3 cases were examined between January 2016 and December 2019. Three patients presented with similar clinical manifestations and radiographic features, with multiple osteolytic lesions in the carpal bones and metacarpal bone base.Diagnoses:The 3 cases were diagnosed as diffuse type tenosynovial giant cell tumor, calcifying aponeurotic fibroma, and rheumatoid arthritis.Interventions:Separate, experienced radiologist and pathologist took part in the interpretation and compartmentalization of radiographs and pathological findings, respectively. Even magnetic resonance imaging could not achieve a diagnosis; surgical excision was therefore required, with subsequent pathological assessment for treatment and final diagnosis.Outcomes:functional outcomes also differed among patients, poorest in rheumatoid arthritis patient.lessons:We report 3 rare disease entities, presenting with multifocal osteolytic lesions in the wrist. They all presented with similar clinical manifestations, and the final diagnoses were made via pathological evaluation. Compared with tenosynovial giant cell tumor and calcifying aponeurotic fibroma, rheumatoid arthritis had the poorest outcome.  相似文献   

17.
Biological therapies represent one of the major advances in the treatment of rheumatoid arthritis in the past decade. The tumour necrosis factor alpha (TNF‐α) inhibitors have started marketing in most Asian countries. Despite having a higher efficacy than conventional disease‐modifying antirheumatic drugs (DMARDs), the anti‐TNF‐α agents are not successful in all patients with rheumatoid arthritis. Moreover, short‐term and long‐term complications such as tuberculous infection and lymphoma are still a major concern. Recent studies have demonstrated that several non‐TNF‐α biologics such as rituximab, abatacept and tocilizumab are effective in patients with refractory rheumatoid arthritis, including those who are not responsive to the TNF‐α inhibitors. This article updates the clinical data on the recently developed non‐TNF‐α biological agents in rheumatoid arthritis.  相似文献   

18.
OBJECTIVE: To determine the nature of the initial changes of joint inflammation occurring before, at the time of, and shortly after onset of clinically apparent arthritis. METHODS: Human tumor necrosis factor (TNF)-transgenic mice were assessed for clinical, histologic, immunophenotypic, serologic, and molecular changes at the preclinical phase of arthritis, at the onset of disease, and at the stage of early clinical disease. In addition, the effects of a genetic osteoclast deficiency and pharmacologic inhibition of TNF were studied in these initial phases of disease. RESULTS: Initial articular changes were observed even before the start of clinical symptoms. Infiltration of the tendon sheaths by granulocytes and macrophages as well as formation of osteoclasts next to the inflamed tendon sheaths were the first pathologic events. Tenosynovitis rapidly led to remodeling of the sheaths into pannus-like tissue, which formed osteoclasts that invaded the adjacent mineralized cartilage. Early lesions were associated with up-regulation of interleukin-1 (IL-1) and IL-6 as well as activation of p38 MAPK and ERK. In contrast, absence of osteoclasts led to uncoupling of tenosynovitis from invasion into cartilage and bone. TNF blockade also attenuated the pathologic changes associated with tenosynovitis. CONCLUSION: Structural damage begins even before the onset of clinical symptoms of arthritis and involves the tendon sheaths as well as adjacent cartilage and bone. These results suggest that tenosynovitis is an initiating feature of arthritis and that joint destruction starts right from the onset of disease. Our findings thus underscore the importance of immediate initiation of an effective therapy in patients with rheumatoid arthritis.  相似文献   

19.
Distal extremity swelling with pitting oedema due to altered lymphatic drainage has been reported in some patients with rheumatoid arthritis (RA). The resistant-to-therapy oedema usually affected the upper limbs in an asymmetrical pattern. Until now, extensor tenosynovial involvement has not been described in RA patients suffering from distal extremity swelling with pitting oedema. Three patients are described: two of them had predominant extensor tenosynovial involvement in their hands, with impaired lymphatic drainage demonstrated by (MRI) and lymphoscintigraphy, respectively. In both cases the oedema was chronic and not responsive to treatment. One patient had extensor tenosynovial involvement without impaired lymphatic drainage. In this case, the oedema remitted completely after a few days of corticosteroid therapy. None of them showed differences in serum levels of vascular endothelial growth factor (VEGF), whether they were RA patients with no pitting oedema or healthy volunteers. Received: 6 January 2000 / Accepted: 20 September 2000  相似文献   

20.
The aim of the study was to analyse the correlations between serum concentrations of the tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2) and clinical markers of the disease activity in patients with early rheumatoid arthritis. The study group consisted of 30 RA patients, untreated with disease modifying anti-rheumatic drugs or corticosteroids, with disease duration less than 3 years. The analysis of serum concentrations of TIMPs was based on a quantitative sandwich ELISA. We found the positive correlations between serum TIMP-1 level and clinical markers of the disease activity such as the Ritchie articular index, erythrocyte sedimentation rate (ESR) and disease activity score (DAS) (in all cases p<0.05). Furthermore, we observed positive correlations between serum TIMP-2 concentration and ESR (p<0.01). We conclude that studied tissue inhibitors of matrix metalloproteinases might be useful clinical markers of the disease activity in early rheumatoid arthritis.  相似文献   

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