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IL-6 pathway-driven investigation of response to IL-6 receptor inhibition in rheumatoid arthritis.

Wang J, Platt A, Upmanyu R, Germer S, Lei G, Rabe C, Benayed R, Kenwright A, Hemmings A, Martin M, Harari O - BMJ Open (2013)

Bottom Line: Our analyses illustrate that the biological activity of a disease-associated molecular pathway may impact the benefit of a therapy targeting that pathway.However, the variation in pathway activity, as measured in blood, may not be a strong predictor.These data suggest that the major contribution to variability in clinical responsiveness to therapeutics in RA remains unknown.

View Article: PubMed Central - PubMed

Affiliation: Roche Products Ltd, Welwyn Garden City, UK.

ABSTRACT

Objectives: To determine whether heterogeneity in interleukin-6 (IL-6), IL-6 receptor and other components of the IL-6 signalling pathway/network, at the gene, transcript and protein levels, correlate with disease activity in patients with rheumatoid arthritis (RA) and with clinical response to tocilizumab.

Design: Biomarker samples and clinical data for five phase 3 trials of tocilizumab were analysed using serum (3751 samples), genotype (927 samples) and transcript (217 samples) analyses. Linear regression was then used to assess the association between these markers and either baseline disease activity or treatment response.

Results: Higher baseline serum IL-6 levels were significantly associated (p<0.0001) with higher baseline DAS28, erythrocyte sedimentation rate, C reactive protein and Health Assessment Questionnaire in patients whose responses to disease-modifying antirheumatic drugs (DMARD-IR) and to antitumour necrosis factor (aTNF-IR) were inadequate and patients who were naive/responders to methotrexate (MTX). Higher baseline serum IL-6 levels were also significantly associated with better clinical response to tocilizumab (versus placebo) measured by cDAS28 in the pooled DMARD-IR (p<0.0001) and MTX-naive populations (p=0.04). However, the association with treatment response was weak. A threefold difference in baseline IL-6 level corresponded to only a 0.17-unit difference in DAS28 at week 16. IL-6 pathway single nucleotide polymorphisms and RNA levels also were not strongly associated with treatment response.

Conclusions: Our analyses illustrate that the biological activity of a disease-associated molecular pathway may impact the benefit of a therapy targeting that pathway. However, the variation in pathway activity, as measured in blood, may not be a strong predictor. These data suggest that the major contribution to variability in clinical responsiveness to therapeutics in RA remains unknown.

No MeSH data available.


Related in: MedlinePlus

Serum interleukin 6 (IL-6) concentration association with response to treatment. Forest plots show the effect and 95% CI for the association of IL-6 with cDAS28 at 16 weeks across treatment lines. cDAS28, change in DAS28 from baseline at week 16; CI; DMARD, disease-modifying antirheumatic drug; IR, inadequate responder; MTX, methotrexate; SD; TCZ, tocilizumab; TNF, tumour necrosis factor; , MTX/DMARD; , TCZ+MTX/DMARD.
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BMJOPEN2013003199F1: Serum interleukin 6 (IL-6) concentration association with response to treatment. Forest plots show the effect and 95% CI for the association of IL-6 with cDAS28 at 16 weeks across treatment lines. cDAS28, change in DAS28 from baseline at week 16; CI; DMARD, disease-modifying antirheumatic drug; IR, inadequate responder; MTX, methotrexate; SD; TCZ, tocilizumab; TNF, tumour necrosis factor; , MTX/DMARD; , TCZ+MTX/DMARD.

Mentions: Higher baseline serum IL-6 concentrations were significantly associated with better clinical response to tocilizumab but not to placebo, as measured by cDAS28 in the pooled DMARD-IR population (p<0.0001; see online supplementary table S2, figure 1). The same effect was observed in the MTX-naive population (p=0.04). In the aTNF-IR population, the association was not significant, partially because of the smaller sample size. In the DMARD-IR population, a threefold difference in baseline IL-6 concentration, equivalent to 1 SD in the baseline log(IL-6) distribution, corresponded to a small difference of 0.17 units in cDAS28 score at week 16. The association between serum IL-6 level and achievement of DAS28 remission (DAS28<2.6) was analysed using receiver operating characteristic analysis in the pooled DMARD-IR population treated with tocilizumab (n=1547). The area under the curve was only 0.59, suggesting that baseline serum IL-6 levels provided very little discrimination between those achieving and those not achieving DAS28 remission. In the placebo group, the direction of association was opposite that of tocilizumab-treated patients, indicating that baseline serum IL-6 level (with no longitudinal data on change in level) is not a prognostic factor for clinical response in RA in these cohorts.


IL-6 pathway-driven investigation of response to IL-6 receptor inhibition in rheumatoid arthritis.

Wang J, Platt A, Upmanyu R, Germer S, Lei G, Rabe C, Benayed R, Kenwright A, Hemmings A, Martin M, Harari O - BMJ Open (2013)

Serum interleukin 6 (IL-6) concentration association with response to treatment. Forest plots show the effect and 95% CI for the association of IL-6 with cDAS28 at 16 weeks across treatment lines. cDAS28, change in DAS28 from baseline at week 16; CI; DMARD, disease-modifying antirheumatic drug; IR, inadequate responder; MTX, methotrexate; SD; TCZ, tocilizumab; TNF, tumour necrosis factor; , MTX/DMARD; , TCZ+MTX/DMARD.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3753518&req=5

BMJOPEN2013003199F1: Serum interleukin 6 (IL-6) concentration association with response to treatment. Forest plots show the effect and 95% CI for the association of IL-6 with cDAS28 at 16 weeks across treatment lines. cDAS28, change in DAS28 from baseline at week 16; CI; DMARD, disease-modifying antirheumatic drug; IR, inadequate responder; MTX, methotrexate; SD; TCZ, tocilizumab; TNF, tumour necrosis factor; , MTX/DMARD; , TCZ+MTX/DMARD.
Mentions: Higher baseline serum IL-6 concentrations were significantly associated with better clinical response to tocilizumab but not to placebo, as measured by cDAS28 in the pooled DMARD-IR population (p<0.0001; see online supplementary table S2, figure 1). The same effect was observed in the MTX-naive population (p=0.04). In the aTNF-IR population, the association was not significant, partially because of the smaller sample size. In the DMARD-IR population, a threefold difference in baseline IL-6 concentration, equivalent to 1 SD in the baseline log(IL-6) distribution, corresponded to a small difference of 0.17 units in cDAS28 score at week 16. The association between serum IL-6 level and achievement of DAS28 remission (DAS28<2.6) was analysed using receiver operating characteristic analysis in the pooled DMARD-IR population treated with tocilizumab (n=1547). The area under the curve was only 0.59, suggesting that baseline serum IL-6 levels provided very little discrimination between those achieving and those not achieving DAS28 remission. In the placebo group, the direction of association was opposite that of tocilizumab-treated patients, indicating that baseline serum IL-6 level (with no longitudinal data on change in level) is not a prognostic factor for clinical response in RA in these cohorts.

Bottom Line: Our analyses illustrate that the biological activity of a disease-associated molecular pathway may impact the benefit of a therapy targeting that pathway.However, the variation in pathway activity, as measured in blood, may not be a strong predictor.These data suggest that the major contribution to variability in clinical responsiveness to therapeutics in RA remains unknown.

View Article: PubMed Central - PubMed

Affiliation: Roche Products Ltd, Welwyn Garden City, UK.

ABSTRACT

Objectives: To determine whether heterogeneity in interleukin-6 (IL-6), IL-6 receptor and other components of the IL-6 signalling pathway/network, at the gene, transcript and protein levels, correlate with disease activity in patients with rheumatoid arthritis (RA) and with clinical response to tocilizumab.

Design: Biomarker samples and clinical data for five phase 3 trials of tocilizumab were analysed using serum (3751 samples), genotype (927 samples) and transcript (217 samples) analyses. Linear regression was then used to assess the association between these markers and either baseline disease activity or treatment response.

Results: Higher baseline serum IL-6 levels were significantly associated (p<0.0001) with higher baseline DAS28, erythrocyte sedimentation rate, C reactive protein and Health Assessment Questionnaire in patients whose responses to disease-modifying antirheumatic drugs (DMARD-IR) and to antitumour necrosis factor (aTNF-IR) were inadequate and patients who were naive/responders to methotrexate (MTX). Higher baseline serum IL-6 levels were also significantly associated with better clinical response to tocilizumab (versus placebo) measured by cDAS28 in the pooled DMARD-IR (p<0.0001) and MTX-naive populations (p=0.04). However, the association with treatment response was weak. A threefold difference in baseline IL-6 level corresponded to only a 0.17-unit difference in DAS28 at week 16. IL-6 pathway single nucleotide polymorphisms and RNA levels also were not strongly associated with treatment response.

Conclusions: Our analyses illustrate that the biological activity of a disease-associated molecular pathway may impact the benefit of a therapy targeting that pathway. However, the variation in pathway activity, as measured in blood, may not be a strong predictor. These data suggest that the major contribution to variability in clinical responsiveness to therapeutics in RA remains unknown.

No MeSH data available.


Related in: MedlinePlus