Molecular therapeutic targets in rheumatoid arthritis

2005 ◽  
Vol 7 (16) ◽  
pp. 1-20 ◽  
Author(s):  
Sandra M. Sacre ◽  
Evangelos Andreakos ◽  
Peter Taylor ◽  
Marc Feldmann ◽  
Brian M. Foxwell
Keyword(s):  
Rheumatoid Arthritis ◽  
Clinical Investigation ◽  
Interleukin 1 ◽  
Therapeutic Targets ◽  
Disease Process ◽  
New Drugs ◽  
Therapeutic Modalities ◽  
Molecular Aspects ◽  
Molecular Therapeutic ◽  
Factor Α

In an attempt to combat the pain and damage generated by rheumatoid arthritis (RA), new drugs are being developed to target molecular aspects of the disease process. Recently, a major development has been the use of biologicals (antibodies and soluble receptors) that neutralise the activity of tumour necrosis factor α (TNF-α) and interleukin 1 (IL-1), both of which are involved in disease progression. An increase in our understanding of cell and molecular biology has resulted in the identification and investigation of potential new targets, and also the refinement and improvement of current therapeutic modalities. This review describes therapies that are approved, in clinical trials or under pre-clinical investigation at the laboratory level, particularly focusing on cytokines, although other therapeutic targets of interest are mentioned.

Carotid Plaque Is Not Associated With Increased Levels of Interleukin 1, Interleukin 6, and Tumor Necrosis Factor α in Rheumatoid Arthritis

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Rosa I. Arvizu-Rivera ◽  
Jose R. Azpiri-Lopez ◽  
Iris J. Colunga-Pedraza ◽  
Jesus A. Cardenas-de la Garza ◽  
Raymundo Vera-Pineda ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Tumor Necrosis Factor ◽  
Interleukin 6 ◽  
Carotid Plaque ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Interleukin 1 ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals Development of Chronic Inflammatory Arthropathy Resembling Rheumatoid Arthritis in Interleukin 1 Receptor Antagonist–Deficient Mice

2000 ◽  
Vol 191 (2) ◽  
pp. 313-320 ◽  
Author(s):  
Reiko Horai ◽  
Shinobu Saijo ◽  
Hidetoshi Tanioka ◽  
Susumu Nakae ◽  
Katsuko Sudo ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Receptor Antagonist ◽  
Interleukin 1 ◽  
Type Ii Collagen ◽  
Cytokine Network ◽  
Gene Deficiency ◽  
Double Stranded Dna ◽  
Inflammatory Arthropathy ◽  
Factor Α ◽  
Deficient Mice

Interleukin (IL)-1 is a proinflammatory cytokine that plays important roles in inflammation, host defense, and the neuro-immuno-endocrine network. IL-1 receptor antagonist (ra) is an endogenous inhibitor of IL-1 and is supposed to regulate IL-1 activity. However, its pathophysiological roles in a body remain largely unknown. To elucidate the roles of IL-1ra, IL-1ra–deficient mice were produced by gene targeting, and pathology was analyzed on different genetic backgrounds. We found that all of the mice on a BALB/cA background, but not those on a C57BL/6J background, spontaneously developed chronic inflammatory polyarthropathy. Histopathology showed marked synovial and periarticular inflammation, with articular erosion caused by invasion of granulation tissues closely resembling that of rheumatoid arthritis in humans. Moreover, elevated levels of antibodies against immunoglobulins, type II collagen, and double-stranded DNA were detected in these mice, suggesting development of autoimmunity. Proinflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor α were overexpressed in the joints, indicating regulatory roles of IL-1ra in the cytokine network. We thus show that IL-1ra gene deficiency causes autoimmunity and joint-specific inflammation and suggest that IL-1ra is important in maintaining homeostasis of the immune system. Possible involvement of IL-1ra gene deficiency in RA will be discussed.

scholarly journals Comparison of Certolizumab Pegol with Other Anticytokine Agents for Treatment of Rheumatoid Arthritis: A Multiple-treatment Bayesian Metaanalysis

2011 ◽  
Vol 38 (5) ◽  
pp. 835-845 ◽  
Author(s):  
ROBERT LAUNOIS ◽  
BERNARD AVOUAC ◽  
FRANCIS BERENBAUM ◽  
OLIVIER BLIN ◽  
ISABELLE BRU ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Interleukin 1 ◽  
Certolizumab Pegol ◽  
Inadequate Response ◽  
Acr20 Response ◽  
Multiple Treatment ◽  
American College Of Rheumatology ◽  
Significant Efficacy ◽  
Treatment Comparisons ◽  
Factor Α

Objective.To compare the clinical efficacy of certolizumab pegol (CZP) with that of other anticytokine agents indicated for the treatment of rheumatoid arthritis (RA) with identical therapeutic indication (anti-tumor necrosis factor-α, anti-interleukin 1 or 6), with the objective of determining the noninferiority of CZP.Methods.A systematic review was performed to identify randomized controlled trials that assessed the efficacy of anticytokine agents in combination with conventional disease-modifying antirheumatic drugs (DMARD) after 6 months of treatment, using the American College of Rheumatology (ACR) response criteria, in patients with RA who have shown inadequate response to DMARD including methotrexate. Indirect treatment comparisons were carried out by a multiple-treatment Bayesian random-effects metaanalysis. Data were analyzed using the Markov chain Monte Carlo simulation. Noninferiority of CZP was assessed in comparison with a predefined equivalence margin of 5%.Results.Nineteen placebo-controlled studies were identified: 14 evaluated the efficacy of 5 anti-TNF-α agents (infliximab, etanercept, adalimumab, golimumab, CZP) and 5 evaluated efficacy of 2 anti-interleukin agents (anakinra, tocilizumab). Every treatment showed significant efficacy versus placebo in individual studies. The multiple-treatment metaanalysis showed a highest OR for CZP on ACR20 response. Metaanalysis indicates that the efficacy of CZP according to ACR20 response is superior to that of infliximab, adalimumab, and anakinra, and equivalent or superior to that of etanercept, golimumab, and tocilizumab. According to ACR50 response, the efficacy of CZP is equivalent or superior to that of all other anticytokines.Conclusion.Results of this original multiple-treatment Bayesian metaanalysis indicate that certolizumab pegol is at least as efficacious as the preexisting antirheumatic anticytokine biotherapies.

Circulating Dickkopf-1 Is Correlated with Bone Erosion and Inflammation in Rheumatoid Arthritis

2011 ◽  
Vol 38 (5) ◽  
pp. 821-827 ◽  
Author(s):  
SHI-YAO WANG ◽  
YAN-YING LIU ◽  
HUA YE ◽  
JIAN-PING GUO ◽  
RU LI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Rheumatic Diseases ◽  
Bone Erosion ◽  
Interleukin 1 ◽  
Healthy Controls ◽  
Serum Samples ◽  
Reactive Protein ◽  
Tnf Α ◽  
Factor Α ◽  
Dickkopf 1

Objective.To explore the potential role of Dickkopf-1 (DKK-1) in rheumatoid arthritis (RA) and to evaluate the effect of a tumor necrosis factor-α (TNF-α) inhibitor (infliximab) and an interleukin 1 receptor antagonist (IL-1Ra; anakinra) on DKK-1 secretion in patients with RA.Methods.Serum samples were collected from 100 patients with RA, 100 patients with other rheumatic diseases (e.g., osteoarthritis and ankylosing spondylitis), and 40 healthy controls. DKK-1 and osteoprotegerin (OPG) levels in serum were detected by ELISA. Serum C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR), rheumatoid factor (RF) titers, and anti-cyclic citrullinated peptide antibody were also measured in patients with RA.Results.The serum level of DKK-1 was significantly higher in patients with RA than in healthy controls and those with other rheumatic diseases (p < 0.01); the serum DKK-1 level was correlated with levels of CRP (r = 0.488, p = 0.003) and ESR (r = 0.458, p = 2.4 x 10−4) and the Sharp score of radiologic change (r = 0.449, p = 0.001) in RA. In contrast to the increasing level of OPG, DKK-1 was significantly decreased in RA patients treated with TNF-α inhibitor (p < 0.01). DKK-1 was significantly decreased in RA patients treated with IL-1Ra (p < 0.01).Conclusion.DKK-1, as an important mediator, was correlated with bone erosion and inflammation in RA. The change of DKK-1 level may serve as a biomarker of disease activity and bone erosion.

scholarly journals Rheumatoid Arthritis: A Novel Approach in Diagnosis and Treatment

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Marina Kostic
Keyword(s):  
Rheumatoid Arthritis ◽  
Structural Changes ◽  
Interleukin 1 ◽  
Treat To Target ◽  
Signal Pathways ◽  
Biological Drugs ◽  
Safety Issues ◽  
Novel Approach ◽  
Post Marketing ◽  
Factor Α

AbstractThe rheumatoid arthritis is chronic disease with progressive course and deteriorations of joints as well as other organs. The pathogenesis of rheumatoid arthritis is characterized with chronic synovitis and inflammation. The main roles in development of rheumatoid arthritis have auto-reactive T cells and inflammatory cytokines, especially tumor necrosis factor α, interleukin 1 and interleukin 6. The management of rheumatoid arthritis has evolved significantly in the past twenty years, especially with introduction new diagnostic criteria by European League for Rheumatoid Arthritis which are very sensitive for early arthritis. The main goal of treating rheumatoid arthritis is to start with therapy in the phase of the disease when destruction of joints can still be prevented. Therapeutic strategies for rheumatoid arthritis involve wide palette of different drugs which can be divided into conventional and biological Disease Modifying Anthirheumatic Drugs. The use of methotrexate in combination with biological drugs provide targeting not only structural changes in rheumatoid arthritis but also and immunological pathways in development of rheumatoid arthritis. These drugs synergistically provide clinical remission and low activity of rheumatoid arthritis in the majority of patients. The uses of biological drugs are limited due their high costs or safety profile. In order to reduce costs and toxicity in the treatment of rheumatoid arthritis, new treat- to –target concept is established. The new class of drugs which modulate signal pathways and activity of tyrosine kinase are under investigations in post marketing surveys in patients with rheumatoid arthritis as in efficacy as in safety issues.

scholarly journals Cloning of the gene for interstitial collagenase-3 (matrix metalloproteinase-13) from rabbit synovial fibroblasts: differential expression with collagenase-1 (matrix metalloproteinase-1)

1998 ◽  
Vol 331 (1) ◽  
pp. 341-346 ◽  
Author(s):  
Matthew P. VINCENTI ◽  
Charles I. COON ◽  
J. Andrew MENGSHOL ◽  
Sue YOCUM ◽  
Peter MITCHELL ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Matrix Metalloproteinase ◽  
Time Course ◽  
Interleukin 1 ◽  
Connective Tissue Diseases ◽  
Synovial Fibroblasts ◽  
Matrix Metalloproteinase 1 ◽  
Rabbit Gene ◽  
Factor Α ◽  
Interstitial Collagenase

Cartilage, bone and the interstitial stroma, composed largely of the interstitial collagens, types I, II and III, are remodelled by three members of the metalloproteinase (MMP) family, collagenase-1 (MMP-1), collagenase-2 (MMP-8) and collagenase-3 (MMP-13). MMP-1 and MMP-13 may contribute directly to disease progression, since they are induced in patients with rheumatoid arthritis and osteoarthritis. The study of MMP-1 and MMP-13 gene regulation in models of arthritic disease has been problematic because mice and rats, which are typically used, only possess a homologue of MMP-13. Here we show that in contrast with mice and rats, rabbits possess distinct genes homologous to human MMP-1 and MMP-13. Furthermore, rabbit MMP-13 is expressed simultaneously with MMP-1 in chondrocytes and synovial fibroblasts in response to the cytokines interleukin-1 and tumour necrosis factor-α, or the phorbol ester PMA. The time course of MMP-13 induction is more rapid and transient than that of MMP-1, suggesting that distinct mechanisms regulate the expression of these two collagenases. We have cloned the rabbit MMP-13 gene from synovial fibroblasts and demonstrated that the rabbit gene shares greater homology with human MMP-13 than does the mouse interstitial collagenase. Together with the fact that mice and rats do not possess a homologue to human MMP-1, our data suggest that the rabbit provides an appropriate model for studying the roles of interstitial collagenases in connective-tissue diseases, such as rheumatoid arthritis and osteoarthritis.

scholarly journals Therapeutic Targets for Bone and Soft-Tissue Sarcomas

2019 ◽  
Vol 20 (1) ◽  
pp. 170 ◽  
Author(s):  
Shinji Miwa ◽  
Norio Yamamoto ◽  
Katsuhiro Hayashi ◽  
Akihiko Takeuchi ◽  
Kentaro Igarashi ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Checkpoint Inhibitors ◽  
Therapeutic Targets ◽  
Soft Tissue Sarcomas ◽  
Science Research ◽  
New Drugs ◽  
Basic Studies ◽  
Molecular Therapeutic ◽  
New Treatments ◽  
Molecular Therapeutic Targets

Due to the rarity and heterogeneity of bone and soft-tissue sarcomas, investigation into molecular targets and new treatments has been particularly challenging. Although intensive chemotherapy and establishment of surgical procedures have improved the outcomes of patients with sarcoma, the curative rate of recurrent and metastatic sarcomas is still not satisfactory. Recent basic science research has revealed some of the mechanisms of progression and metastasis of malignancies including proliferation, apoptosis, angiogenesis, tumor microenvironment, migration, invasion, and regulation of antitumor immune systems. Based on these basic studies, new anticancer drugs, including pazopanib, trabectedin, eribulin, and immune checkpoint inhibitors have been developed and the efficacies and safety of the new drugs have been assessed by clinical trials. This review summarizes new molecular therapeutic targets and advances in the treatment for bone and soft tissue sarcomas.

scholarly journals Osteoblast role in the pathogenesis of rheumatoid arthritis

2021 ◽  
Vol 48 (3) ◽  
pp. 2843-2852
Author(s):  
S. Berardi ◽  
A. Corrado ◽  
N. Maruotti ◽  
D. Cici ◽  
F. P. Cantatore
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Loss ◽  
Current Knowledge ◽  
Interleukin 1 ◽  
Inflammatory Factors ◽  
Bone Homeostasis ◽  
Factor Α ◽  
And Function ◽  
Maximal Reduction

AbstractIn the pathogenesis of several rheumatic diseases, such as rheumatoid arthritis, spondyloarthritis, osteoarthritis, osteoporosis, alterations in osteoblast growth, differentiation and activity play a role. In particular, in rheumatoid arthritis bone homeostasis is perturbed: in addition to stimulating the pathologic bone resorption process performed by osteoclasts in course of rheumatoid arthritis, proinflammatory cytokines (such as Tumor Necrosis factor-α, Interleukin-1) can also inhibit osteoblast differentiation and function, resulting in net bone loss. Mouse models of rheumatoid arthritis showed that complete resolution of inflammation (with maximal reduction in the expression of pro-inflammatory factors) is crucial for bone healing, performed by osteoblasts activity. In fact, abnormal activity of factors and systems involved in osteoblast function in these patients has been described. A better understanding of the pathogenic mechanisms involved in osteoblast dysregulation could contribute to explain the generalized and focal articular bone loss found in rheumatoid arthritis. Nevertheless, these aspects have not been frequently and directly evaluated in studies. This review article is focused on analysis of the current knowledge about the role of osteoblast dysregulation occurring in rheumatoid arthritis: a better knowledge of these mechanisms could contribute to the realization of new therapeutic strategies.

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