Inflammation, Asthma, and Tumor Necrosis Factor-alpha

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tnf alpha diagramby Erwin W. Gelfand, MD

Patients with severe and refractory asthma suffer from numerous complications, fatal disease, and utilize a large proportion of healthcare resources. Treatment options are certainly limited, and it is unclear what underlies their refractoriness to conventional therapy. Whether they are "resistant" to therapy with glucocorticoids or the pathophysiologic pathways involved in their disease are not sensitive to glucocorticoids is unclear at present.

Some phenotypic differences in patients with refractory asthma have emerged, such as a greater involvement of neutrophils, but the relevance of these data are not clear. Among the candidates identified as perhaps playing a role in refractory asthma is tumor necrosis factor-alpha (TNF-alpha), a pleiotropic inflammatory cytokine that is expressed in mast cells[1] and is present in higher concentrations in bronchoalveolar fluid from patients with asthma, particularly in bronchoalveolar lavage (BAL) fluid from patients with more severe asthma.[2]

TNF-alpha and Asthma

TNF-alpha has served as a major therapeutic target in a number of chronic inflammatory conditions, generally involving neutrophils, and include rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, Crohn's disease, psoriasis, glomerulonephritis, sarcoidosis, and Behcet's disease.[1] All of these diseases have a tendency toward a predominant Th1 response and all with a link to high levels of production of TNF-alpha.

It therefore seems incongruous that asthma and airway eosinophilia, thought of as a Th2 disease, may also have some link with asthma. At least in mouse models of asthma deficiencies in TNF-alpha, deficiencies in expression of TNF-alpha receptors, treatment with anti- TNF-alpha antibody, or induction of TNF-alpha autoantibody result in attenuation of antigen-induced airway hyperresponsiveness and eosinophilic airway inflammation.[2,3] Inhalation of TNF-alpha in rodents[4] and humans, normals, or asthmatics[5,6] did trigger altered airway function (bronchial hyperresponsiveness) together with airway neutrophilia. Genetic associations have linked TNF-alpha gene polymorphisms and bronchial hyperresponsiveness and asthma.[7,8]

Many different cell types release TNF-alpha, including T cells, monocytes/macrophages, mast cells, eosinophils, and epithelial cells. Beyond the recruitment of neutrophils, TNF-alpha sustains lung inflammatory responses by increasing the expression of adhesion molecules, accounting for the increased accumulation of neutrophils and eosinophils in the airways. Their activation by TNF-alpha triggers the release of cytotoxic mediators and toxic products of reactive oxygen and nitrogen, further damaging the airways.[9] TNF-alpha also contributes to airway remodeling by inducing activation and proliferation of fibroblasts, subepithelial fibrosis, production of extracellular matrix glycoproteins, and goblet cell metaplasia.[10] TNF-alpha also has direct effects on airway reactivity to methacholine or allergen, as shown in isolated tracheal ring experiments.[11]

Given these effects of TNF-alpha on airway inflammation and reactivity, selective inhibition of TNF-alpha would provide important information about its role in asthma in general and severe, refractory asthma in particular. There are currently a number of inhibitors available with extensive clinical experience in inflammatory disorders. The inhibitors include the monoclonal antibodies against TNF-alpha (infliximab and adalimumab) as well as the soluble TNF-alpha receptor fused to human immunoglobulin (Ig)G (etanercept).[1,12] These agents were shown to suppress inflammation, slow progression of disease, and strikingly induce remission in certain patients with rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, and psoriasis.[1]

Targeting TNF-alpha

Because of the unmet need in patients with severe, persistent asthma, the potential of targeting TNF-alpha has been explored in 3 recent studies. In the first study, Howarth and colleagues[13] demonstrated that TNF-alpha levels in the airways were related to the severity of asthma. Despite the use of high-dose corticosteroid therapy, the levels of expression of the TNF-alpha gene and protein in BAL fluid, and numbers of TNF-alpha immunoreactive cells, were higher in the airways of asthmatics with refractory disease than in the airways of control subjects or patients with milder disease. In an open-label trial of etanercept (soluble TNF-alpha receptor) for 3 months, treated patients had some improvement in measures of airflow, symptom scores, and bronchial hyperresponsiveness. Seventeen patients were recruited, and 15 completed the 12-week study. Paired sputum samples from 8 of 11 subjects showed reductions in eosinophil and neutrophil numbers, but failed to achieve statistical significance. The mean increase from baseline forced expiratory volume in 1 second (FEV1) values was 240 mL with morning and evening peak expiratory flow (PEF) percentage predicted) increasing 6% and 8%, respectively.

In a similar study, Berry and colleagues[14] measured markers of TNF-alpha activation in 10 patients with mild-to-moderate asthma and 10 control subjects. In addition, the effects of treatment with etanercept were evaluated in 10 patients with refractory asthma for 10 weeks in a randomized, double-blind, crossover study. The results showed that in patients with refractory asthma, there was increased expression of membrane-bound TNF-alpha, TNF receptor 1, and TNF-alpha-converting enzyme by peripheral blood monocytes. In the patients who completed the 10-week trial, treatment with etanercept reduced the expression of membrane-bound TNF-alpha in peripheral blood monocytes as well as demonstrated improvement in PC20, asthma-related quality-of-life scores, FEV1, and symptom scores. Of note, the baseline expression of membrane-bound TNF-alpha by peripheral blood monocytes and the extent to which it was reduced by etanercept treatment were independently associated with the net improvement in the primary outcome measures (PC20 and asthma quality-of-life scores).

In a third study,[15] infliximab was used in a double-blind, placebo-controlled, parallel group design. Thirty-eight patients with moderate asthma and treated with inhaled corticosteroids were enrolled and were symptomatic during the run-in phase. Infliximab was administered at weeks 0, 2, and 6 with evaluation at week 8. The primary endpoint, change in morning PEF at days 50-56 compared with the last 7 days of the run-in, was not significantly different on treatment. There were also no treatment differences in FEV1, rescue beta2-agonist use, or in asthma symptom scores. In addition, there were no differences in markers of inflammation, including exhaled nitric oxide, blood eosinophil counts, or sputum cell composition. Infliximab treatment did reduce levels or TNF-alpha, interleukin (IL)-1alpha, IL-6, human interferon inducible protein (IP)-10, and IL-8 but not eotaxin in sputum supernates. Treatment with infliximab was associated with some reduction in asthma exacerbations and diurnal variation of the peak expiratory flow (PEF) rate. The study authors concluded that infliximab did not demonstrate significant clinical efficacy in primary endpoint lung function in these patients with symptomatic moderate asthma. Whether the apparent lack of benefit in this study compared to the 2 earlier studies represents differences in the pharmacology of targeting TNF-alpha with a monoclonal antibody (infliximab) or soluble receptors (etanercept) remains to be determined.

These studies suffer from the very short duration of the trials and the small numbers of patients who completed the full course of therapy. It is therefore important to await the results of much larger, multicenter, and well-designed trials before embarking on this expensive therapy in individual patients with refractory asthma. Patients with refractory asthma require novel therapeutic approaches to control their disease, especially when conventional therapy, including corticosteroids, fails. Whether targeting TNF-alpha will provide one such avenue awaits further study.

References

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