Diverse effects of infliximab and etanercept on T lymphocytes

doi:10.1016/j.semarthrit.2005.01.006

Seminars in Arthritis and Rheumatism

Volume 34, Issue 5, Supplement 1, April 2005, Pages 23-27

https://doi.org/10.1016/j.semarthrit.2005.01.006 Get rights and content

The tumor necrosis factor (TNF) antagonists infliximab and etanercept have proven to be useful additions to the armamentarium of agents used to manage patients with inflammatory disorders. However, as discussed in detail elsewhere in this supplement, these agents have different mechanisms of action and distinct safety and efficacy profiles in the clinical setting. Of particular interest are differing effects on T lymphocytes, thymocyte-derived cells that are responsible for cell-mediated immunity. Recent studies in 2 disease states, ankylosing spondylitis and Crohn’s disease, have assessed the effects of TNF antagonists on T lymphocytes and reported differences that could partially explain some of the clinical disparities that have been reported.

Section snippets

Efficacy and safety

Ankylosing spondylitis (AS) is an inflammatory disease of the spine for which there are very few effective treatments available (1). A role for the tumor necrosis factor (TNF) antagonists infliximab and etanercept has been proposed, based the known presence of TNFα in the inflamed sacroiliac joints of patients with AS and other spondyloarthritides, and the evidence of efficacy in other arthritides (eg, psoriatic arthritis, rheumatoid arthritis) and AS-associated diseases (ie, inflammatory bowel

Efficacy and safety

Additional data regarding the effects of TNF antagonists on T-cell function has come from research in Crohn’s disease (CD), a chronic inflammatory disorder of the gastrointestinal tract in which the activity and efficacy profiles of infliximab and etanercept are known to be different. Infliximab is effective in CD; it can be used to induce or maintain remission and treat fistulizing disease. In a 12-week multicenter, randomized, double-blind, placebo-controlled trial of single infusions of

Clinical implications of reduced T-cell function

In addition to influencing the clinical activity of these agents in CD, differing effects on T lymphocytes could influence safety and tolerability. For example, reports of a lupus-like syndrome among infliximab-treated patients could be the result of compensatory T-cell activation (in response to prolonged reduction in T-cell cytokine production), and subsequent formation of ANA. While a clear association has not been established, ANA formation has been reported following infliximab therapy for

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Certolizumab, a fully humanized anti-TNF inhibitor, with the advantage of a once a month subcutaneous injection,160 has been reported to cause two events of uveitis in one patient in a 96-week ongoing, multicenter, open-label, phase 4 study.226 Infliximab and adalimumab inhibit TNF- α, but etanercept inhibits both TNF- α and TNF-β and unlike the other agents.198 This difference may partly explain the observed differences in their efficacy and side effect profile.
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As expected, we found a significant reduction of TNFα in the PBMC supernatants by infliximab; surprisingly, however, incubation with etanercept on the contrary strongly enhanced the TNFα levels. These data are somewhat in contrast to other reports, which described also in vitro a reduction of TNFα by etanercept; these discrepancies to our results could be explained by different in vitro conditions as concentrations of TNFα-blockers or cell lines used by the authors [52,53]. Furthermore, the action of etanercept on membrane as well as soluble TNFα is ‘reversible’, whereas the binding of monoclonal anti-TNFα antibodies is more effective [2,3,12], i.e. dissociation of etanercept and TNFα could have lead to increased TNFα levels in the cell culture supernatants.
The tumor necrosis factor-alpha (TNFα) antagonists infliximab or etanercept are used in the management of chronic inflammatory disorders but have differences in clinical activity. Here we show that both have different effects on immunocompetent cells in vitro.
Peripheral blood mononuclear cells (PBMC) from 20 healthy donors were incubated with infliximab or etanercept alone and in a co-culture with recall-antigens (BCG, tetanus toxoid [TT]). Expression of the activation marker CD69 on different PBMC-subpopulations was determined by flow cytometry, release of Th1-, Th2- and macrophage/monocyte-related cytokines into the supernatants by ELISA.
There were strong inter-individual differences in reactivity of PBMC of the 20 donors towards infliximab and etanercept. On the whole group level, both enhanced IL-10 production but had opposite effects on the TNFα- and IFNγ-secretion; Th2-cytokine-secretion (IL-13, IL-5) was differentially influenced. IL-13 production was significantly reduced by infliximab but not by etanercept. IL-5 secretion was strongly enhanced in individual subjects but was not significantly influenced on the whole group level. Etanercept but not infliximab significantly decreased the CD69-expression by CD8+ T- and CD56+ natural killer(NK)-cells. Co-culture with recall antigens enhanced most of these reactions.
Our data indicate that individual predisposition and immunological reactivity may be an important factor influencing the therapeutic efficacy of anti-TNFα agents.
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Psoriasis vulgaris is an inflammatory skin disease that is generally chronic and that affects between 1% and 2% of the population in industrialized Western countries. It is associated with a marked decline in quality of life. A wide range of treatments are currently available, although surveys conducted before the advent of biologic agents reflected a strong degree of dissatisfaction with the treatments then available. Extensive scientific evidence has been gathered on the safety of biologic agents, and this has led to a review of the role of systemic treatment in general and has allowed new therapeutic goals and strategies to be contemplated in patients with moderate to severe psoriasis. In this new situation, there is a need for Spanish guidelines on the treatment of moderate to severe psoriasis with biologic agents, drafted by consensus among specialists and ratified by the Spanish Psoriasis Group of the Spanish Academy of Dermatology and Venereology (AEDV). These guidelines should be evidence-based with regard to the pharmacologic characteristics, mechanism of action, administration route and regimen, efficacy, contraindications, adverse effects, and cost estimates of biologic agents approved for the treatment of moderate to severe psoriasis in Spain.
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In human biopsies and in rat allografts on day 6 with acute allograft rejection, significantly elevated expression of TNFR2 was observed in tubular epithelial cells, podocytes, B cells and monocytes/macrophages. The expression level was associated with renal function. The TNFR2 expression level at day 28 was significantly lower compared to day 6.
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Citation Excerpt :
Infliximab, a monoclonal antibody directed at TNFα, binds to both soluble and membrane-bound TNFα, resulting in clearance of both circulating TNFα and T cells.14 Etanercept, a soluble dimeric TNFα receptor 2, competes for TNFα binding and renders it inactive.14,15 This mechanism of action combined with its relative ease of administration by subcutaneous injection and generally minor side effects,15 make etanercept attractive as primary GVHD therapy.
Graft-versus-host disease (GVHD) is a principal cause of morbidity following allogeneic hematopoietic cell transplantation (HCT). Standard therapy for GVHD, high-dose steroids, results in complete responses (CRs) in 35% of patients. Because tumor necrosis factor-α (TNFα) is an important effector of experimental GVHD, we treated patients with new-onset GVHD with steroids plus the TNFα inhibitor etanercept on a previously reported pilot trial (n = 20) and a phase 2 trial (n = 41). We compared their outcomes with those of contemporaneous patients with GVHD (n = 99) whose initial therapy was steroids alone. Groups were similar with respect to age, conditioning, donor, degree of HLA match, and severity of GVHD at onset. Patients treated with etanercept were more likely to achieve CR than were patients treated with steroids alone (69% vs 33%; P < .001). This difference was observed in HCT recipients of both related donors (79% vs 39%; P = .001) and unrelated donors (53% vs 26%; P < .001). Plasma TNFR1 levels, a biomarker for GVHD activity, were elevated at GVHD onset and decreased significantly only in patients with CR. We conclude that etanercept plus steroids as initial therapy for acute GVHD results in a substantial majority of CRs. This trial was referenced at www.clinicaltrials.gov as NCT00141713.

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Diverse effects of infliximab and etanercept on T lymphocytes

Section snippets

Efficacy and safety

Efficacy and safety

Clinical implications of reduced T-cell function

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Therapy of ankylosing spondylitis and other spondyloarthritidesestablished medical treatment, anti-TNF-alpha therapy and other novel approaches

Arthritis Res

New treatment options in spondyloarthropathiesincreasing evidence for significant efficacy of anti-tumor necrosis factor therapy

Curr Opin Rheumatol

Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitisan open, observational, extension study of a three-month, randomized, placebo-controlled trial

Arthritis Rheum

Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis, before and after successful therapy with infliximabevaluation of a new scoring system

Arthritis Rheum

Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) versus placebo in active spondylarthropathy

Arthritis Rheum

Anti-tumour necrosis factor alpha therapy for ankylosing spondylitisinternational experience

Ann Rheum Dis

Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor alpha monoclonal antibody infliximab

Arthritis Rheum