Demyelination occurring during anti-tumor necrosis factor ? therapy for inflammatory arthritides

Mohan, Niveditha; Edwards, Evelyne T.; Cupps, Thomas R.; Oliverio, Patrick J.; Sandberg, Glenn D.; Crayton, Heidi; Richert, John R.; Siegel, Jeffrey

doi:10.1002/1529-0131(200112)44:12<2862::aid-art474>3.0.co;2-w

Cited by 752 publications

(449 citation statements)

References 29 publications

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“…Although anti-TNF␣ therapy seems to be generally well tolerated, severe side effects of both etanercept and infliximab have occurred in some rare cases (42)(43)(44)(45). The actual status of reported adverse events can be obtained from the FDA Web site at www.fda.gov.…”

Section: Discussionmentioning

confidence: 99%

Six‐month results of a double‐blind, placebo‐controlled trial of etanercept treatment in patients with active ankylosing spondylitis

Brandt

Khariouzov

Listing

et al. 2003

Arthritis & Rheumatism

420

271

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Objective. There is increasing evidence that tumor necrosis factor ␣ (TNF␣) is centrally involved in the pathogenesis of ankylosing spondylitis (AS) and other spondylarthritides. This study was designed to investigate the efficacy of anti-TNF␣ therapy with etanercept, a 75-kd receptor fusion protein, in active AS.Methods. This multicenter trial had 2 phases: an initial placebo-controlled period of 6 weeks' duration and an observational phase lasting 24 weeks. Thirty patients with active AS were included. They were randomized into 2 groups, which received either etanercept (25 mg twice weekly) (n ‫؍‬ 14) or placebo (n ‫؍‬ 16) for 6 weeks. Then both groups were treated with etanercept. Nonsteroidal antiinflammatory drug (NSAID) treatment could be continued, but disease-modifying antirheumatic drugs (DMARDs) and steroids had to be withdrawn prior to the study. All patients received etanercept for a total of 12 weeks and were followed up for at least 24 weeks. The Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index, Bath AS Metrology Index, pain level on a numeric rating scale, quality of life by the Short Form 36, and C-reactive protein (CRP) level were assessed. The primary outcome parameter was a >50% improvement in the BAS-DAI.Results. Treatment with etanercept resulted in at least a 50% regression of disease activity in 57% of these patients at week 6, versus 6% of the placebo-treated patients (P ‫؍‬ 0.004). After the placebo-treated patients switched to etanercept, 56% improved. The mean ؎ SD BASDAI improved from 6.5 ؎ 1.2 at baseline to 3.5 ؎ 1.9 at week 6 in the etanercept group, with no improvement in the placebo group (P ‫؍‬ 0.003 between groups). Similarly, pain, function, mobility, and quality of life improved with etanercept but not with placebo at week 6 (P < 0.05). Mean CRP levels decreased significantly with etanercept but not with placebo (P ‫؍‬ 0.001). There was ongoing improvement in all parameters in both groups until week 12 and week 18, respectively (i.e., throughout the period of etanercept treatment). Disease relapses occurred a mean ؎ SD of 6.2 ؎ 3.0 weeks after cessation of etanercept. No severe adverse events, including major infections, were observed during the trial.Conclusion. This study shows that on a shortterm basis (3 months), treatment with etanercept is clearly efficacious in patients with active AS who are receiving NSAID therapy but not DMARDs or steroids. After cessation of therapy, almost all patients experienced a relapse within a few weeks. Thus, it seems probable that etanercept must be administered continuously in most AS patients to achieve permanent inhibition of the inflammatory process.Ankylosing spondylitis (AS), the prototype of the spondylarthritides (SpA), is a chronic inflammatory rheumatic disease. In the past, the prevalence of SpA has been underestimated (1); more recently, the prevalence of the group of SpA as a whole has been calculated

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Section: Discussionmentioning

confidence: 99%

Six‐month results of a double‐blind, placebo‐controlled trial of etanercept treatment in patients with active ankylosing spondylitis

Brandt

Khariouzov

Listing

et al. 2003

Arthritis & Rheumatism

420

271

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“…Several patients treated with TNF antagonists have developed multiple sclerosis [91]. Others with multiple sclerosis have had exacerbations of their disease when treated with these agents.…”

Section: A C C E P T E D Article In Pressmentioning

confidence: 99%

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

Matera

Calzetta

Cazzola

2010

Pulmonary Pharmacology & Therapeutics

117

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Tumor necrosis factor (TNF)-α, a pleiotropic cytokine that exerts a variety of effects, such as growth promotion, growth inhibition, angiogenesis, cytotoxicity, inflammation, and immunomodulation, has been implicated in several inflammatory conditions. It plays a significant role in many inflammatory diseases of lung. Given that there is significant literature supporting the pathobiologic role of TNF-α in asthma, mainly in severe refractory asthma, and COPD, TNF-α inhibitors (infliximab, golimumab and etanercept) are now regarded as potential new medications in asthma and COPD management. The studies reported in literature indicate that TNF-α inhibitors are effective in a relatively small subgroup of patients with severe asthma, possibly defined by an increased TNF axis, but they seem to be ineffective in COPD, although an observational study demonstrated that TNF-α inhibitors were associated with a reduction in the rate of COPD hospitalisation among patients with COPD receiving these agents to treat their rheumatoid arthritis. These findings require a smart approach because there is still good reason to target TNF-α, perhaps in a more carefully selected patient group. TNF-α treatment should therefore not be thrown out, or abandoned. Indeed, since severe asthma and COPD are heterogeneous diseases that have characteristics that occur with different phenotypes remained poorly characterized and little known about the underlying pathobiology contributing to them, it is likely that definition of these phenotypes and choice of the right outcome measure will allow us to understand which kind of patients can benefit from TNF-α inhibitors.

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“…T umor necrosis factor (TNF) is a multipotent inflammatory cytokine that plays an important role in the pathogenesis of diseases caused by autoimmune T cell responses, not only as a stimulatory mediator (1)(2)(3)(4), but also as an inhibitor in certain settings (5)(6)(7). Excess TNF has been associated with rheumatoid arthritis (RA) and other forms of inflammatory autoimmune diseases.…”

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confidence: 99%

“…Humanized anti-TNF antibodies have been reported to be of benefit in the treatment of the above diseases as well as psoriasis and Crohn's disease. Overall, it is evident that anti-TNF therapy results in a moderate to dramatic decrease in RA symptoms, and in some cases a near complete remission, although the disease recurs relatively promptly after cessation of anti-TNF therapy (3,8).…”

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confidence: 99%

Genomic expression profiling of TNF-α-treated BDC2.5 diabetogenic CD4⁺T cells

Lee

Lih²,

Huang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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TNF-␣ plays an important role in immune regulation, inflammation, and autoimmunity. Chronic TNF exposure has been shown to downmodulate T cell responses. In a mouse T cell hybridoma model, TNF attenuated T cell receptor (TCR) signaling. We have confirmed that chronic TNF and anti-TNF exposure suppressed and increased T cell responses, respectively. In adult TCR (BDC2.5) transgenic nonobese diabetic mice, DNA microarray analysis of global gene expression in BDC2.5 CD4 ؉ T cells in response to chronic TNF or anti-TNF exposure showed that genes involved in functional categories including T cell signaling, cell cycle, proliferation, ubiquitination, cytokine synthesis, calcium signaling, and apoptosis were modulated. Genes such as ubiquitin family genes, cytokine inducible Src homology 2-containing genes, cyclin-dependent kinase inhibitors p21, p57, calmodulin family genes (calmodulin-1, -2, and -3) and calcium channel voltage-dependent, N type ␣1B subunit (CaV2.2) were induced by TNF, whereas Vav2, Rho GTPase-activating protein, calcium channel voltage-dependent, L type ␣1C subunit (CaV1.2), IL-1 receptor-associated kinase-1 and -2, and IL enhancer binding factor 3 were reduced by TNF. Genes such as CaV1.2 and proliferating cell nuclear antigen, repressed by TNF, were induced by anti-TNF treatment. Further, we showed that chronic TNF exposure impaired NF-B and adaptor protein 1 transactivation activity, leading to T cell unresponsiveness. Thus, our results present a detailed picture of transcriptional programs affected by chronic TNF exposure and provide candidate target genes that may function to mediate TNF-induced T cell unresponsiveness.

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Demyelination occurring during anti-tumor necrosis factor ? therapy for inflammatory arthritides

Cited by 752 publications

References 29 publications

Six‐month results of a double‐blind, placebo‐controlled trial of etanercept treatment in patients with active ankylosing spondylitis

Six‐month results of a double‐blind, placebo‐controlled trial of etanercept treatment in patients with active ankylosing spondylitis

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

Genomic expression profiling of TNF-α-treated BDC2.5 diabetogenic CD4⁺T cells

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Demyelination occurring during anti-tumor necrosis factor ? therapy for inflammatory arthritides

Cited by 752 publications

References 29 publications

Six‐month results of a double‐blind, placebo‐controlled trial of etanercept treatment in patients with active ankylosing spondylitis

Six‐month results of a double‐blind, placebo‐controlled trial of etanercept treatment in patients with active ankylosing spondylitis

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

Genomic expression profiling of TNF-α-treated BDC2.5 diabetogenic CD4+T cells

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Genomic expression profiling of TNF-α-treated BDC2.5 diabetogenic CD4⁺T cells