TNF-blocking Drugs Research Articles

Signaling via TNFR2 mediates CNS remyelination in EAE through regulation of oligodendrocyte progenitor cells

Abstract Tumor necrosis factor-alpha (TNF) is a pleiotropic inflammatory cytokine that has been associated with the pathogenesis of several autoimmune diseases, including multiple sclerosis (MS). Consequently, TNF-blocking drugs have been widely used to treat many inflammatory conditions and have proven highly effective. However, treatment of MS patients with anti-TNF drugs leads to disease exacerbation and severe demyelination. This effect has been specifically associated with lack of TNF signaling through its receptor, TNFR2. However, the underlying mechanisms are not fully understood. Experimental autoimmune encephalomyelitis (EAE) is the most common animal model used to study MS. Our lab has recently generated TNFR2−/− DR2b+/+ mice to study the role of TNFR2 signaling in EAE in the context of the HLA-DR2b (DRB1*1501), a haplotype strongly associated with MS. We found that these mice developed progressive EAE characterized by increased demyelinating lesions. Strikingly, this phenotype was not due to lack of TNFR2 expression in T cells, but rather was associated with a decreased numbers of oligodendrocyte progenitor cells (OPCs) in the CNS. Moreover, we demonstrated that TNFR2 signaling is critical for expression of chemokines in the CNS, suggesting its involvement in OPC function and recruitment. Our studies provide key insights into CNS repair and regulatory mechanisms controlled by TNF during inflammation, and this information may help develop novel therapeutic strategies.

Intra-articular therapy with tumor necrosis factor-α antagonists: an update

The aim of the study was to review from the present literature the intra-articular (IA) use of the TNF-blocking drugs. A total of 28 papers about this topic were found through a search in PubMed; the first publication's date was July 2003. These studies include a total of 214 patients affected by 12 different joint diseases that reported a total of 1046 intra-articular therapies carried out in 10 different joint sites. Infliximab and etanercept were the most widely used medications. The safety of this treatment clearly emerges from our analysis, while more difficult was the evaluation of its efficacy. Nevertheless we deduced an ideal patient profile that may better respond to the IA anti-TNF treatment.

SAT0113 Intense Repression of Serum Oxidative Stress Marker in Rheumatoid Arthritis Cases Treated with Tocilizumab: Cross Sectional and Longitudinal Evaluation

BackgroundOxidative stress induced by reactive oxygen species (ROS) is also an important mechanism that underlies destructive and proliferative synovitis in rheumatoid arthritis (RA). Abundant amounts of reactive oxygen species have...

TNF receptor 1 gene variant could explain failure of TNF-blocking drugs in multiple sclerosis

Multiple sclerosis: TNF receptor 1 gene variant could explain failure of TNF-blocking drugs in multiple sclerosis

TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis

Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS)1, it has been difficult to demonstrate which variants are causal and what role they play in disease. Moreover, the modest contribution these variants make to disease risk has raised questions regarding their medical relevance2. We have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes TNF receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS)3,4, but not with other autoimmune conditions such as rheumatoid arthritis (RA)5, psoriasis6 and Crohn’s disease7. By analyzing MS GWAS3,4 data in conjunction with the 1000 Genomes Project data8 we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF blocking drugs can promote onset or exacerbation of MS9-11, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.

Apoptosis as a Mechanism of Action of Tumor Necrosis Factor Antagonists in Rheumatoid Arthritis: Figure 1.

Tumor necrosis factor (TNF) antagonists are drugs developed to block endogenous TNF, an essential proinflammatory molecule with a central role in the pathogenesis of rheumatoid arthritis (RA). Although extensive studies have been performed concerning the mode of action of TNF-blocking agents, there are still many unresolved questions and potential differences between different TNF-blocking drugs. One unresolved issue is to what extent apoptosis is affected by TNF blockade in RA. We provide an overview of studies that have investigated the proapoptotic effect of different anti-TNF drugs in RA, searching for a unified interpretation of somewhat contradictory data.

Practical Management and Monitoring of Psoriasis Patients on Biologic Therapy: A Survey of Opinion Leaders and Practitioners

Objective To provide practical guidance to dermatologists on how to monitor psoriasis patients on biologic therapies. Design Survey of health care providers on monitoring and vaccination practices in patients on biologic therapies. Participants 21 present and former members of the Medical Board of the National Psoriasis Foundation. Results The survey revealed a wide variety of practices, but some general trends emerged. Most of the experts who were surveyed checked screening hematology with all of the drugs and continued to check it every two to six months. CD4+ counts were only checked with alefacept and were generally taken at screening and at least every two weeks. Serum chemistry and liver function monitoring were usually checked at screening and then every two to six months, especially in patients on infliximab. Most of the practitioners surveyed did not check for antinuclear antibodies (ANA) at screening. However, approximately one-third did screen for ANA in patients on tumor necrosis factor (TNF)-blocking agents; only a few continued to check it every three to six months. Tuberculosis screening was generally done for patients on all of the biologic therapies, but was almost universally done in patients treated with TNF-blocking drugs. Yearly tuberculin skin testing was continued by approximately two-thirds of the practitioners. Approximately half of respondents gave influenza vaccines to patients on biologic therapy. Conclusions Currently there are no guidelines for the monitoring of patients on biologic therapy and there is a lack of consistency among practitioners. However, medical literature provides a great deal of information on which to base monitoring practices. Monitoring and vaccination practices should vary from patient to patient depending on many factors, so these findings should not be viewed as guidelines.

Tumor Necrosis Factor Blockade: Mechanism of Action

Modulation of the immune response with tumor necrosis factor (TNF) blockers is not a new treatment strategy for many inflammatory disorders; however, relatively little is known about their specific mechanism of action. Understanding the mode of action, pharmacology, and pharmacokinetics of the monoclonal TNF antibodies, infliximab and adalimumab, and the soluble TNF receptor, etanercept, may therefore enable us to account for their differing clinical profiles. The aim of this supplement is to explore the roles and mechanisms of TNF and TNF blockade using in vitro pharmacological and in vivo animal modeling experiments, and in vivo studies of the effects of etanercept on the inflammatory cascade in patients with psoriasis.

Aspects of early arthritis. Biological therapy in early arthritis--overtreatment or the way to go?

The availability of newer, and more expensive, therapies for patients with rheumatoid arthritis has changed treatment beyond recognition. Disease remission is the goal for all new patients. Studies have shown that a combination of tumour necrosis factor (TNF)-blocking drugs and methotrexate produces superior outcomes over monotherapy alone; however, use is limited by cost and potential side-effects. Currently, anti-TNF therapy is normally reserved for patients who have failed traditional disease-modifying anti-rheumatic drugs. The question that remains is whether TNF-blocking drugs are better used if given early; the high direct costs are countered by both direct and indirect savings in healthcare costs from optimal control of disease, and the benefits of early control outweigh the increased risk of infection and malignancy.

Effectiveness of anakinra in rheumatic disease in patients naive to biological drugs or previously on TNF blocking drugs: an observational study

The aim of this study was to evaluate the effectiveness of IL-1 inhibition in rheumatic disease using real-life, observational methods. We analyzed data from 47 patients collected from the national ROB-FIN for rheumatic disease. Commonly used, validated measures of efficacy and adverse effects were documented and analyzed. The series contains 47/1,135 patients (mean age 47+/-11 years, range 25-73, females 83%) on anakinra of whom 39 patients suffered from rheumatoid arthritis (RA), two presented with psoriatic arthritis, and four with juvenile RA. At 3 months (26/40), 46% reached American College of Rheumatology (ACR) 20 and 27% ACR 50. In patients naive to biological drugs, the response rate at 3 months was 60% for ACR 20 and 20% for ACR 50. At follow-up of the total series, ACR responses at 6 and 12 months were 69/56% for ACR 20 and 23/22% for ACR 50. These data give room for IL-1 suppression when treating patient with rheumatic disease. Careful selection of patients, together with combining anakinra with disease-modifying antirheumatic drugs, perhaps adds effectiveness. For treating clinicians in Finland, these results are encouraging, as reimbursed treatment alternatives for patients refractory to all other therapies are still few.

Impact of concomitant DMARD therapy on adherence to treatment with etanercept and infliximab in rheumatoid arthritis. Results from a six-year observational study in southern Sweden

The objective of this work is to compare the adherence to therapy of patients receiving etanercept and infliximab during first tumour necrosis factor (TNF)-blocking treatment course in rheumatoid arthritis. Special emphasis is placed on potential predictors for treatment termination and the impact of concomitant methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs). Patients (n = 1,161) with active rheumatoid arthritis, not responding to at least two DMARDs including MTX starting etanercept or infliximab therapy for the first time, were included in a structured clinical follow-up protocol. Information on diagnosis, disease duration, previous and ongoing DMARDs, treatment start and termination, as well as cause of withdrawal was prospectively collected during the period of March 1999 through December 2004. Patients were divided into six groups according to TNF-blocking drugs and concomitant DMARDs. Five-year level (one-year) of adherence to therapy was 36% (69%) for patients receiving infliximab in combination with MTX compared with 65% (89%) for patients treated with etanercept and MTX (p < 0.001). Cox regression models showed that the risk for premature treatment termination of patients treated with infliximab was threefold higher than for etanercept (p < 0.001). Also, the regression analysis showed that patients receiving concomitant MTX had better treatment continuation than patients treated solely with TNF blockers (p < 0.001). Moreover, patients receiving concomitant MTX had superior drug survival than patients receiving other concomitant DMARDs (p < 0.010). The superior effect of MTX was associated primarily with fewer treatment terminations because of adverse events. In addition, the study identifies low C-reactive protein level, high age, elevated health assessment questionnaire score, and higher previous number of DMARDs as predictors of premature treatment termination. In summary, treatment with etanercept has higher adherence to therapy than treatment with infliximab. Concomitant MTX is associated with improved treatment continuation of biologics when compared with both TNF blockers as monotherapy and TNF blockers combined with other DMARDs.

TNF Inhibition Rapidly Down-Regulates Multiple Proinflammatory Pathways in Psoriasis Plaques

The mechanisms of action of marketed TNF-blocking drugs in lesional tissues are still incompletely understood. Because psoriasis plaques are accessible to repeat biopsy, the effect of TNF/lymphotoxin blockade with etanercept (soluble TNFR) was studied in ten psoriasis patients treated for 6 months. Histological response, inflammatory gene expression, and cellular infiltration in psoriasis plaques were evaluated. There was a rapid and complete reduction of IL-1 and IL-8 (immediate/early genes), followed by progressive reductions in many other inflammation-related genes, and finally somewhat slower reductions in infiltrating myeloid cells (CD11c+ cells) and T lymphocytes. The observed decreases in IL-8, IFN-gamma-inducible protein-10 (CXCL10), and MIP-3alpha (CCL20) mRNA expression may account for decreased infiltration of neutrophils, T cells, and dendritic cells (DCs), respectively. DCs may be less activated with therapy, as suggested by decreased IL-23 mRNA and inducible NO synthase mRNA and protein. Decreases in T cell-inflammatory gene expression (IFN-gamma, STAT-1, granzyme B) and T cell numbers may be due to a reduction in DC-mediated T cell activation. Thus, etanercept-induced TNF/lymphotoxin blockade may break the potentially self-sustaining cycle of DC activation and maturation, subsequent T cell activation, and cytokine, growth factor, and chemokine production by multiple cell types including lymphocytes, neutrophils, DCs, and keratinocytes. This results in reversal of the epidermal hyperplasia and cutaneous inflammation characteristic of psoriatic plaques.

BSR guidelines for prescribing TNF-α blockers in adults with ankylosing spondylitis. Report of a working party of the British Society for Rheumatology

Two TNF-blocking drugs are now licensed for the treatment of ankylosing spondylitis (AS) and there is clear evidence of symptomatic efficacy. It is recognized that the instruments for analysing aspects of AS and the outcomes of treatment are imperfect, though they are validated and adequate for the purpose. This document provides guidance to enable consultant rheumatologists in the UK to balance the demonstrated merits of TNF blockade treatment against the known and unknown potential toxicity. Background AS is an inflammatory condition primarily affecting the spine. Onset is most common in the third decade of life, though the disease may remain symptomatic and progressive throughout life. It is part of the family of spondyloarthropathies, which also includes psoriatic arthritis, reactive arthritis and enteropathic arthritis. Undifferentiated forms of spondyloarthopathy, often presenting as mono- or oligoarthritis, are also recognized, as are juvenile forms of spondyloarthopathy, in which the spine is not affected but may become so later. Thus, many individuals with AS also suffer from involvement of the hips, peripheral joints and peripheral entheses as well as periodic eye inflammation, inflammatory bowel disease and psoriasis. The treatment of axial and peripheral elements of this disease therefore requires distinct criteria and guidance that is specific for the particular feature. Symptoms may persist throughout adult life, though some patients experience a diminution of symptoms or even remission of active disease after a period of years. The consequences of active spinal disease, including spinal stiffness or rigidity and increased risk of spinal fracture, are irreversible.

What will treatment of autoimmune diseases entail in 2010?

“Everyone overestimates the changes that will occur in I year but underestimates the changes that will occur in a decade” is one of the favourite quotations of Bill Gates. If this quotation is true, we probably underestimate the changes in the treatment of the autoimmune diseases rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) that will occur in the next decade. In particular, in RA we have witnessed great changes between 1990 and 2000 with the dramatic step of abandoning the pyramid strategy in the treatment of this disease and the unforeseen availability to almost all rheumatologists of TNF blocking drugs. Thus, the afore-mentioned quotation may also be valid for the field of the autoimmune diseases.