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Circulating tumour necrosis factor-alpha bioactivity in rheumatoid arthritis patients treated with infliximab: link to clinical response.

Marotte H, Maslinski W, Miossec P - Arthritis Res. Ther. (2004)

Bottom Line: With plasma samples obtained before the first infusion, the IL-6-induced production was greater in patients with a good clinical response than in the poor responders (44.4 +/- 23.3 ng/ml versus 27.4 +/- 20.9 ng/ml; P = 0.05).The difference between IL-6 levels induced with plasma samples obtained before and 4 hours after the first infusion was greater in patients with a good clinical response (40.0 +/- 23.7 ng/ml versus 3.4 +/- 10.0 ng/ml; P = 0.001).Levels of circulating TNF-alpha bioactivity were predictive of clinical response to TNF-alpha inhibition, confirming a key role for TNF-alpha in these RA patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology and Unité Mixte Hospices Civils de Lyon-BioMérieux, Hôpital Edouard Herriot, Lyon, France.

ABSTRACT
Our objective was to clarify the heterogeneity in response to infliximab treatment in rheumatoid arthritis (RA); to this end, a bioassay was designed to explore the contribution of circulating tumour necrosis factor (TNF)-alpha bioactivity and its possible link to response. The bioassay is based on the induction of IL-6 and osteoprotegerin (OPG) production by synoviocytes in response to TNF-alpha. RA synoviocytes were cultured with TNF-alpha (5 ng/ml) and 42 RA plasma samples collected just before starting therapy. Levels of IL-6 and OPG were measured in supernatants. In 20 of the patients, plasma samples collected before and 4 hours after the first and the ninth infusions were tested in the same way. Plasma concentrations of TNF-alpha and p55 and p75 soluble receptors were measured using ELISA. TNF-alpha induced IL-6 and OPG production by synoviocytes, which was further increased with patient plasma dilutions and inhibited by infliximab. With plasma samples obtained before the first infusion, the IL-6-induced production was greater in patients with a good clinical response than in the poor responders (44.4 +/- 23.3 ng/ml versus 27.4 +/- 20.9 ng/ml; P = 0.05). This high circulating TNF-alpha bioactivity was strongly inhibited with the first infliximab infusion. The difference between IL-6 levels induced with plasma samples obtained before and 4 hours after the first infusion was greater in patients with a good clinical response (40.0 +/- 23.7 ng/ml versus 3.4 +/- 10.0 ng/ml; P = 0.001). Similar findings were obtained for OPG production (7.0 +/- 6.2 ng/ml versus 0.0 +/- 3.0 ng/ml; P < 0.05). Levels of circulating TNF-alpha bioactivity were predictive of clinical response to TNF-alpha inhibition, confirming a key role for TNF-alpha in these RA patients.

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Principle of the bioassay. Rheumatoid arthritis synoviocytes (104 cells/well) were cultured in 96-well plates and stimulated with increasing doses of tumour necrosis factor (TNF)-α (0–100 ng/ml). Levels of (a) IL-6 and (b) osteoprotegerin (OPG) were measured in 48-hour supernatants. Infliximab at 10 μg/ml was preincubated for 1 hour with TNF-α before its addition to the culture.
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Figure 1: Principle of the bioassay. Rheumatoid arthritis synoviocytes (104 cells/well) were cultured in 96-well plates and stimulated with increasing doses of tumour necrosis factor (TNF)-α (0–100 ng/ml). Levels of (a) IL-6 and (b) osteoprotegerin (OPG) were measured in 48-hour supernatants. Infliximab at 10 μg/ml was preincubated for 1 hour with TNF-α before its addition to the culture.

Mentions: The principle of the bioassay, as shown in Fig. 1, is based on the ability of TNF-α to induce IL-6 and OPG production by RA synoviocytes. With TNF-α concentrations ranging from 0.1 to 100 ng/ml, IL-6 production by synoviocytes increased in a dose-dependent manner. Addition of infliximab at 10 μg/ml completely inhibited the effect of TNF-α at 1 ng/ml, and reduced that of TNF-α at 10 ng/ml by 74% (32.9 ng/ml without versus 8.5 ng/ml with infliximab; Fig. 1a). Similar studies were performed for OPG production. As for IL-6, OPG production by synoviocytes increased in a dose-dependent manner in response to TNF-α (Fig. 1b). Maximal concentrations of IL-6 and OPG were in the same range up to 35 ng/ml. With regard to IL-6, addition of infliximab inhibited OPG production induced by TNF-α at 10 ng/ml.


Circulating tumour necrosis factor-alpha bioactivity in rheumatoid arthritis patients treated with infliximab: link to clinical response.

Marotte H, Maslinski W, Miossec P - Arthritis Res. Ther. (2004)

Principle of the bioassay. Rheumatoid arthritis synoviocytes (104 cells/well) were cultured in 96-well plates and stimulated with increasing doses of tumour necrosis factor (TNF)-α (0–100 ng/ml). Levels of (a) IL-6 and (b) osteoprotegerin (OPG) were measured in 48-hour supernatants. Infliximab at 10 μg/ml was preincubated for 1 hour with TNF-α before its addition to the culture.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1064892&req=5

Figure 1: Principle of the bioassay. Rheumatoid arthritis synoviocytes (104 cells/well) were cultured in 96-well plates and stimulated with increasing doses of tumour necrosis factor (TNF)-α (0–100 ng/ml). Levels of (a) IL-6 and (b) osteoprotegerin (OPG) were measured in 48-hour supernatants. Infliximab at 10 μg/ml was preincubated for 1 hour with TNF-α before its addition to the culture.
Mentions: The principle of the bioassay, as shown in Fig. 1, is based on the ability of TNF-α to induce IL-6 and OPG production by RA synoviocytes. With TNF-α concentrations ranging from 0.1 to 100 ng/ml, IL-6 production by synoviocytes increased in a dose-dependent manner. Addition of infliximab at 10 μg/ml completely inhibited the effect of TNF-α at 1 ng/ml, and reduced that of TNF-α at 10 ng/ml by 74% (32.9 ng/ml without versus 8.5 ng/ml with infliximab; Fig. 1a). Similar studies were performed for OPG production. As for IL-6, OPG production by synoviocytes increased in a dose-dependent manner in response to TNF-α (Fig. 1b). Maximal concentrations of IL-6 and OPG were in the same range up to 35 ng/ml. With regard to IL-6, addition of infliximab inhibited OPG production induced by TNF-α at 10 ng/ml.

Bottom Line: With plasma samples obtained before the first infusion, the IL-6-induced production was greater in patients with a good clinical response than in the poor responders (44.4 +/- 23.3 ng/ml versus 27.4 +/- 20.9 ng/ml; P = 0.05).The difference between IL-6 levels induced with plasma samples obtained before and 4 hours after the first infusion was greater in patients with a good clinical response (40.0 +/- 23.7 ng/ml versus 3.4 +/- 10.0 ng/ml; P = 0.001).Levels of circulating TNF-alpha bioactivity were predictive of clinical response to TNF-alpha inhibition, confirming a key role for TNF-alpha in these RA patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology and Unité Mixte Hospices Civils de Lyon-BioMérieux, Hôpital Edouard Herriot, Lyon, France.

ABSTRACT
Our objective was to clarify the heterogeneity in response to infliximab treatment in rheumatoid arthritis (RA); to this end, a bioassay was designed to explore the contribution of circulating tumour necrosis factor (TNF)-alpha bioactivity and its possible link to response. The bioassay is based on the induction of IL-6 and osteoprotegerin (OPG) production by synoviocytes in response to TNF-alpha. RA synoviocytes were cultured with TNF-alpha (5 ng/ml) and 42 RA plasma samples collected just before starting therapy. Levels of IL-6 and OPG were measured in supernatants. In 20 of the patients, plasma samples collected before and 4 hours after the first and the ninth infusions were tested in the same way. Plasma concentrations of TNF-alpha and p55 and p75 soluble receptors were measured using ELISA. TNF-alpha induced IL-6 and OPG production by synoviocytes, which was further increased with patient plasma dilutions and inhibited by infliximab. With plasma samples obtained before the first infusion, the IL-6-induced production was greater in patients with a good clinical response than in the poor responders (44.4 +/- 23.3 ng/ml versus 27.4 +/- 20.9 ng/ml; P = 0.05). This high circulating TNF-alpha bioactivity was strongly inhibited with the first infliximab infusion. The difference between IL-6 levels induced with plasma samples obtained before and 4 hours after the first infusion was greater in patients with a good clinical response (40.0 +/- 23.7 ng/ml versus 3.4 +/- 10.0 ng/ml; P = 0.001). Similar findings were obtained for OPG production (7.0 +/- 6.2 ng/ml versus 0.0 +/- 3.0 ng/ml; P < 0.05). Levels of circulating TNF-alpha bioactivity were predictive of clinical response to TNF-alpha inhibition, confirming a key role for TNF-alpha in these RA patients.

Show MeSH
Related in: MedlinePlus