TNF-α as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis

2005 ◽  
Vol 109 (2) ◽  
pp. 135-142 ◽  
Author(s):  
Cristina Russo ◽  
Riccardo Polosa
Keyword(s):  
Rheumatoid Arthritis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Allergen Challenge ◽  
Treatment Modalities ◽  
Tnf Α ◽  
Factor Α

TNF-α (tumour necrosis factor-α) is known to play a critical role in the pathogenic mechanisms of a number of chronic inflammatory diseases, including RA (rheumatoid arthritis), Crohn's disease and psoriasis. The notion that TNF-α is released in allergic responses from both mast cells and macrophages via IgE-dependent mechanisms, the demonstration that elevated levels of TNF-α are frequently observed in bronchoalveolar fluid of asthmatic subjects undergoing allergen challenge and the results from exposure studies of TNF-α in vivo showing increases in airway responsiveness in both normal and asthmatic subjects emphasize the importance of TNF-α in the initiation of allergic asthmatic airway inflammation and the generation of airway hyper-responsiveness. Drugs targeting TNF-α have been developed to neutralize the deleterious effects of this inflammatory cytokine and have proved to be safe and effective in the treatment of patients with RA, Crohn's disease and psoriasis refractory to conventional treatments. Biological therapies blocking TNF-α are likely to constitute a considerable advance in the management of those difficult cases of asthma that are particularly resistant to typical treatment modalities. In this review article, we intend to address the potential role of TNF-α in asthma and to put forward the idea that drugs that have been developed to neutralize the deleterious effects of TNF-α may also be useful in the management of chronic severe asthma.

scholarly journals The effect of marine oil-derived n-3 fatty acids on transepithelial calcium transport in Caco-2 cell models of healthy and inflamed intestines

2007 ◽  
Vol 97 (2) ◽  
pp. 281-288 ◽  
Author(s):  
Jennifer Gilman ◽  
Kevin D. Cashman
Keyword(s):  
Fatty Acids ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Human Subjects ◽  
Healthy Human ◽  
Marine Oil ◽  
Ca Transport ◽  
Tnf Α

Marine oil-derived n-3 fatty acids have been shown to stimulate intestinal Ca absorption in animal studies, but the effects of such fatty acids on Ca absorption in human subjects are relatively unknown. In particular, n-3 fatty acids may be of therapeutic value for some Crohn's disease patients who experience Ca malabsorption. Therefore, the aim of the present study was to investigate the effect of 20 : 5n-3 and 22 : 6n-3 on transepithelial Ca transport across monolayers of healthy Caco-2 cells as well as of TNF-α-treated Caco-2 cells (an in vitro model of Crohn's disease). Caco-2 cells were seeded onto permeable filter supports and allowed to differentiate into monolayers, which were treated with 80 μm-20 : 5n-3, 80 μm-22 : 6n-3, or 40 μm-20 : 5n-3+40 μm-22 : 6n-3 for 6 or 8 d, with or without co-treatment with TNF-α (10 ng/ml) (n 11–15 monolayers per treatment). On day 16, transepithelial and transcellular transport of 45Ca and fluorescein transport (a marker of paracellular diffusion) were measured. Treatment of healthy and inflamed Caco-2 cells with 20 : 5n-3, 22 : 6n-3 and both fatty acids combined for 8 d significantly (P < 0·005–0·01) increased total transepithelial Ca transport compared with that in control, effects which were mediated by an enhanced rate of transcellular Ca transport. The effects of n-3 fatty acids on Ca absorption after 6 d were less clear-cut. In conclusion, the present in vitro findings highlight the need to investigate the effect of marine oil-based n-3 fatty acids on Ca absorption in vivo in studies of healthy human subjects as well as of Crohn's disease patients.

scholarly journals Fulminant Herpes Simplex Hepatitis Secondary to Adalimumab in Crohn’s Disease: A Case Report

2019 ◽  
Vol 12 ◽  
pp. 117954761985897 ◽  
Author(s):  
Kanika Goel ◽  
Mark Bunker ◽  
Anna Balog ◽  
Jan F Silverman
Keyword(s):  
Crohn’S Disease ◽  
Case Report ◽  
Herpes Simplex ◽  
Crohn's Disease ◽  
Rare Case ◽  
Treatment Modalities ◽  
Tnf Α ◽  
Inflammatory Bowel ◽  
Simplex Virus ◽  
Necrosis Factor

Herpes simplex virus (HSV) hepatitis is an uncommon cause of fulminant hepatic failure, seen mostly in immunocompromised patients. Conventional treatment modalities for inflammatory bowel disease (IBD), such as steroids and azathioprine, have been known to cause HSV hepatitis. However, the reported incidence of HSV hepatitis in IBD patients undergoing tumor necrosis factor (TNF)-α inhibitor therapy is very rare. In this case report, we describe a rare case of fulminant HSV hepatitis that developed in a patient with Crohn’s disease after treatment with the TNF-α inhibitor, adalimumab.

scholarly journals Could Polyphenols Help in the Control of Rheumatoid Arthritis?

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1589 ◽  
Author(s):  
Sung ◽  
Kwon ◽  
Um ◽  
Kim
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Diseases ◽  
Mitogen Activated Protein Kinase ◽  
Bone Damage ◽  
Autoimmune Inflammatory Disease ◽  
Novel Drugs ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Α ◽  
Therapeutic Alternatives

Rheumatoid arthritis (RA) is a chronic, systemic, joint-invading, autoimmune inflammatory disease, which causes joint cartilage breakdown and bone damage, resulting in functional impairment and deformation of the joints. The percentage of RA patients has been rising and RA represents a substantial burden for patients around the world. Despite the development of many RA therapies, because of the side effects and low effectiveness of conventional drugs, patients still need and researchers are seeking new therapeutic alternatives. Polyphenols extracted from natural products are effective on several inflammatory diseases, including RA. In this review polyphenols are classified into four types: flavonoids, phenolic acids, stilbenes and others, among which mainly flavonoids are discussed. Researchers have reported that anti-RA efficacies of polyphenols are based mainly on three mechanisms: their anti-inflammatory, antioxidant and apoptotic properties. The main RA factors modified by polyphenols are mitogen-activated protein kinase (MAPK), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), nuclear factor κ light chain enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinases (JNK). Polyphenols could be potent alternative RA therapies and sources for novel drugs for RA by affecting its key mechanisms.

scholarly journals Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-α production in vivo

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 637-641 ◽  
Author(s):  
Rukhsana Aslam ◽  
Edwin R. Speck ◽  
Michael Kim ◽  
Andrew R. Crow ◽  
K. W. Annie Bang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Critical Role ◽  
Receptor Expression ◽  
Tlr4 Expression ◽  
Antiplatelet Antibody ◽  
Tnf Α ◽  
Intracellular Compartments ◽  
Thrombin Activation ◽  
Factor Α

AbstractToll-like receptors (TLRs) play a critical role in stimulating innate immunity by recognizing pathogen-associated molecular patterns (PAMPs) on invading microorganisms. Platelets also play a role in innate immunity, and we studied whether they express TLR. Results show that human and murine platelets variably expressed TLR2, TLR4, and TLR9 by flow cytometry and Western blotting. TLR4 expression was confirmed by demonstrating murine platelet binding to lipopolysaccharide (LPS). Thrombin activation of the platelets significantly enhanced the expression of TLR9, suggesting that at least some TLRs may derive from intracellular compartments. When LPS was administered to LPS-sensitive C3H/HeN and LPS-resistant C3H/HeJ mice, functional TLR4 expression in vivo was shown to be responsible for LPS-induced thrombocytopenia. However, when the C3H/HeN mice were first rendered thrombocytopenic by an antiplatelet antibody and then administered LPS, a significant reduction occurred in their ability to produce TNF-α. The decreased cytokine production in the thrombocytopenic mice was restored with platelet transfusion. These results suggest that platelets express various TLRs and that the functional significance of one of these, TLR4, appears to be a role in the modulation of LPS-induced thrombocytopenia and TNF-α production. This work implicates platelets as important mediators of innate immune responses against invading microorganisms.

scholarly journals Understanding the Molecular Drivers of Disease Heterogeneity in Crohn’s Disease Using Multi-omic Data Integration and Network Analysis

2020 ◽  
Author(s):  
Padhmanand Sudhakar ◽  
Bram Verstockt ◽  
Jonathan Cremer ◽  
Sare Verstockt ◽  
João Sabino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Data Integration ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Treatment Modalities ◽  
Disease Heterogeneity ◽  
Molecular Features ◽  
Genes Encoding

Abstract Crohn’s disease (CD), a form of inflammatory bowel disease (IBD), is characterized by heterogeneity along multiple clinical axes, which in turn impacts disease progression and treatment modalities. Using advanced data integration approaches and systems biology tools, we studied the contribution of CD susceptibility variants and gene expression in distinct peripheral immune cell subsets (CD14+ monocytes and CD4+ T cells) to relevant clinical traits. Our analyses revealed that most clinical traits capturing CD heterogeneity could be associated with CD14+ and CD4+ gene expression rather than disease susceptibility variants. By disentangling the sources of variation, we identified molecular features that could potentially be driving the heterogeneity of various clinical traits of CD patients. Further downstream analyses identified contextual hub proteins such as genes encoding barrier functions, antimicrobial peptides, chemokines, and their receptors, which are either targeted by drugs used in CD or other inflammatory diseases or are relevant to the biological functions implicated in disease pathology. These hubs could be used as cell type–specific targets to treat specific subtypes of CD patients in a more individualized approach based on the underlying biology driving their disease subtypes. Our study highlights the importance of data integration and systems approaches to investigate complex and heterogeneous diseases such as IBD.

scholarly journals Cost-effectiveness and Clinical Outcomes of Early Anti–Tumor Necrosis Factor–α Intervention in Pediatric Crohn’s Disease

2019 ◽  
Vol 26 (8) ◽  
pp. 1239-1250
Author(s):  
Naazish S Bashir ◽  
Thomas D Walters ◽  
Anne M Griffiths ◽  
Shinya Ito ◽  
Wendy J Ungar
Keyword(s):  
Health Care ◽  
Crohn’S Disease ◽  
Cost Effectiveness ◽  
Crohn's Disease ◽  
Incremental Cost ◽  
Standard Care ◽  
Public Health Care ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Abstract Background Anti–tumor necrosis factor–α (anti-TNF-α) treatments are increasingly used to treat pediatric Crohn’s disease, even without a prior trial of immunomodulators, but the cost-effectiveness of such treatment algorithms has not been formally examined. Drug plan decision-makers require evidence of cost-effectiveness to inform funding decisions. The objective was to assess the incremental cost-effectiveness of early intervention with anti-TNF-α treatment vs a conventional step-up strategy per steroid-free remission-week gained from public health care and societal payer perspectives over 3 years. Methods A probabilistic microsimulation model was constructed for children with newly diagnosed moderate to severe Crohn’s disease receiving anti-TNF-α treatment and concomitant treatments within the first 3 months of diagnosis compared with children receiving standard care consisting of steroids and/or immunomodulators with the possibility of anti-TNF-α treatment after 3 months of diagnosis. A North American multicenter observational study with 360 patients provided input into clinical outcomes and health care resource use. Results Early intervention with anti-TNF-α treatment was more costly, with an incremental cost of CAD$31,112 (95% confidence interval [CI], $2939–$91,715), and more effective, with 11.3 more weeks in steroid-free remission (95% CI, 10.6–11.6) compared with standard care, resulting in an incremental cost per steroid-free remission-week gained of CAD$2756 from an Ontario public health care perspective and CAD$2968 from a societal perspective. The incremental cost-effectiveness ratio was sensitive to the price of infliximab. Conclusions The results suggest that although early anti-TNF-α was not cost-effective, it was clinically beneficial. These findings, along with other randomized controlled trial evidence, may inform formulary decision-making.

Impact of smoking on the effectiveness of TNF-α inhibitors in patients with rheumatoid arthritis or Crohn's disease

2014 ◽  
Vol 22 (2) ◽  
pp. 92
Author(s):  
Im-Sook Song ◽  
Hyun Soon Sohn ◽  
Hyunah Kim ◽  
Eunjeong Lim ◽  
Mihwa Kwon ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Tnf Α

Mucosal Expression of Basic Fibroblastic Growth Factor, Syndecan 1 and Tumour Necrosis Factor-α in Crohn’s Disease in Deep Remission under Treatment with Anti-TNFα Antibodies

2014 ◽  
Vol 23 (3) ◽  
pp. 261-265 ◽  
Author(s):  
Antonio Tursi ◽  
Walter Elisei ◽  
Mariabeatrice Principi ◽  
Cosimo Damiano Inchingolo ◽  
Rosanna Nenna ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Growth Factor ◽  
Crohn's Disease ◽  
Control Group ◽  
Rt Pcr ◽  
Molecular Pattern ◽  
Tnf Α ◽  
Factor Α ◽  
Basic Fibroblastic Growth Factor ◽  
Necrosis Factor

Background & Aims: Both inflammation and fibrosis may be detected in Crohn's disease (CD). The molecular pattern of Basic Fibroblastic Growth Factor (bFGF) and Syndecan-1 (SD1) expression is altered in stenosing CD, but we do not know what the behaviour of this teamwork factor is in CD in deep remission under treatment with anti-TNFα antibodies. Our aim was to compare the expression of bFGF, SD1 and TNF-α in patients with CD in deep remission under treatment with Infliximab (IFX) or Adalimumab (ADA) and a control group of patients with active CD.Methods: We assessed the expression of bFGF, SD1 and TNF-α in 10 patients with active CD and in 28 patients with CD in sustained deep remission for at least 6 months. All patients underwent surveillance colonoscopy with biopsies, while receiving maintenance therapy with IFX or ADA. Analysis was conducted by real-time reverse transcriptase PCR (RT-PCR) in biopsy samples.Results: We found that bFGF, SD1 and TNF-α were significantly reduced under treatment with anti-TNFα versus controls (p=0.000). bFGF and SD1 expression were similar between IFX and ADA patients (p=0.335 and p=0.289, respectively), while TNF-α was significantly under-expressed in ADA patients (p=0.008).Conclusions: bFGF, SD1 and TNF-α are significantly reduced in CD patients in deep remission under treatment with anti-TNFα, likely as an expression of optimal control of inflammation. The significance of the TNF-α under-expression in patients under treatment with ADA with respect to those under treatment with IFX should be elucidated in further studies.

scholarly journals Biological Drug Treatment of Rheumatoid Arthritis and Spondyloarthritis: Effects on QT Interval and QT Dispersion

2011 ◽  
Vol 39 (1) ◽  
pp. 41-45 ◽  
Author(s):  
MANUELA DI FRANCO ◽  
MICHELE PARADISO ◽  
FULVIA CECCARELLI ◽  
ROSSANA SCRIVO ◽  
FRANCESCA ROMANA SPINELLI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Qt Interval ◽  
Inflammatory Diseases ◽  
Clinical Manifestations ◽  
Qt Dispersion ◽  
Cardiac Complications ◽  
Standard Procedures ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Objective.Tumor necrosis factor-α (TNF-α) antagonists bring about significant improvement in chronic inflammatory diseases such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). There is some evidence that they can also have negative myocardial effects, but to date this issue has not been clarified. We evaluated changes in electrocardiographic measures [QT interval, corrected, dispersion, and dispersion corrected (QT, QTc, QTd, QTdc, respectively)] in patients with RA or SpA treated with anti-TNF agents (infliximab and etanercept), those treated with other biological agents (rituximab), and with methotrexate.Methods.We studied 38 consecutive patients with RA (21 patients) or SpA (19 patients) being treated with TNF-α antagonists, 8 patients with RA being treated with rituximab, and 13 patients (8 with RA and 5 with SpA) taking methotrexate. Electrocardiographs (ECG) were performed on all participants at baseline and 12 months after initiation of treatment, and the QT, QTc, and QTd were calculated with standard procedures.Results.After 12 months of treatment, significant increases over baseline values were observed in the mean QT (p < 0.009), QTd (p < 0.0001), and QTdc (p < 0.0001) of the anti-TNF group, but no significant changes were observed in those taking rituximab. QT changes in the anti-TNF group were unrelated to the disease (RA vs SpA) or drug (infliximab vs etanercept), and none were associated with clinical manifestations of cardiac disease.Conclusion.In patients with RA and SpA, TNF-α antagonists seem to increase the QT and QTd measures. Although these changes were completely asymptomatic, ECG may be indicated in patients being considered for anti-TNF therapy to identify those at risk for cardiac complications.

Sign in / Sign up

Export Citation Format

Share Document