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The need for prognosticators in rheumatoid arthritis. Biological and clinical markers: where are we now?

Smolen JS, Aletaha D, Grisar J, Redlich K, Steiner G, Wagner O - Arthritis Res. Ther. (2008)

Bottom Line: It will be shown that the relationship of many biomarkers with disease characteristics is confounded by factors unrelated to the disease, and that only few biomarkers exist with some predictive value.Moreover, clinical markers appear of equal value as biomarkers for this purpose, although they likewise have limited capacity in these regards.The analysis suggests the search for better markers to predict outcomes and therapeutic responsiveness in rheumatoid arthritis needs to be intensified.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. josef.smolen@meduniwien.ac.at

ABSTRACT
Rheumatoid arthritis is a heterogeneous disease with respect to clinical manifestations, serologic abnormalities, joint damage and functional impairment. Predicting outcome in a reliable way to allow for strategic therapeutic decision-making as well as for prediction of the response to the various therapeutic modalities available today, especially biological agents, would provide means for optimization of care. In the present article, the current information on biological and clinical markers related to disease activity and joint damage as well as for predictive purposes is reviewed. It will be shown that the relationship of many biomarkers with disease characteristics is confounded by factors unrelated to the disease, and that only few biomarkers exist with some predictive value. Moreover, clinical markers appear of equal value as biomarkers for this purpose, although they likewise have limited capacity in these regards. The analysis suggests the search for better markers to predict outcomes and therapeutic responsiveness in rheumatoid arthritis needs to be intensified.

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Threshold hypothesis of osteoclast activation. (a) Osteoclast activation is assumed to occur only after passing a putative threshold. (b) Anti-TNF therapy may ideally lead to total inhibition of bioactive TNF. (c) In other patients, anti-TNF therapy may reduce TNF activity below the threshold of osteoclast activation; these patients may continue having signs and symptoms of rheumatoid arthritis. (d) In yet another group of patients, the TNF activity may be reduced, but not to a level that goes below the threshold of osteoclast activation; in these patients, there will be more inflammation than in (c) and some residual destruction – in relation to other therapies, such as methotrexate, the destruction will be significantly less at a similar level of inflammatory signs and symptoms of rheumatoid arthritis [79]. CDAI, Clinical Disease Activity Index; CRP, C-reactive protein.
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Figure 3: Threshold hypothesis of osteoclast activation. (a) Osteoclast activation is assumed to occur only after passing a putative threshold. (b) Anti-TNF therapy may ideally lead to total inhibition of bioactive TNF. (c) In other patients, anti-TNF therapy may reduce TNF activity below the threshold of osteoclast activation; these patients may continue having signs and symptoms of rheumatoid arthritis. (d) In yet another group of patients, the TNF activity may be reduced, but not to a level that goes below the threshold of osteoclast activation; in these patients, there will be more inflammation than in (c) and some residual destruction – in relation to other therapies, such as methotrexate, the destruction will be significantly less at a similar level of inflammatory signs and symptoms of rheumatoid arthritis [79]. CDAI, Clinical Disease Activity Index; CRP, C-reactive protein.

Mentions: In this context it needs to be borne in mind that TNF and IL-6 are cytokines that promote osteoclast differentiation and activation [20,21,74-77]. Importantly, under stable low concentrations of RANKL, increasing amounts of proinflammatory cytokines, such as TNF, will lead to increasing osteoclast differentiation [78]. It is therefore conceivable that this relation of TNF levels and osteoclast activation also exists in vivo. In support of this notion, treatment of RA patients with a TNF inhibitor plus methotrexate leads to a dissociation of the close relationship between joint damage and the inflammatory response (exemplified by disease activity measures) [79], and these data were meanwhile confirmed with another TNF-blocker [80]. These findings have led to the threshold hypothesis shown in Figure 3. According to this hypothesis, TNF will lead to joint damage especially once its levels exceed a particular threshold that lies above the threshold needed for the activation of the inflammatory response. Blocking of TNF may inhibit its bioactivity fully (Figure 3b), may reduce bioactivity to levels below the putative threshold of destruction with residual signs and symptoms but no destruction (Figure 3c), or may reduce bioactivity to levels above that threshold but still significantly retard joint damage compared with other treatment modalities, without preventing progression in full (Figure 3d). This hypothesis is in line with results from clinical trials where the use of TNF inhibitors significantly retarded or halted joint destruction despite residual active disease [81-83].


The need for prognosticators in rheumatoid arthritis. Biological and clinical markers: where are we now?

Smolen JS, Aletaha D, Grisar J, Redlich K, Steiner G, Wagner O - Arthritis Res. Ther. (2008)

Threshold hypothesis of osteoclast activation. (a) Osteoclast activation is assumed to occur only after passing a putative threshold. (b) Anti-TNF therapy may ideally lead to total inhibition of bioactive TNF. (c) In other patients, anti-TNF therapy may reduce TNF activity below the threshold of osteoclast activation; these patients may continue having signs and symptoms of rheumatoid arthritis. (d) In yet another group of patients, the TNF activity may be reduced, but not to a level that goes below the threshold of osteoclast activation; in these patients, there will be more inflammation than in (c) and some residual destruction – in relation to other therapies, such as methotrexate, the destruction will be significantly less at a similar level of inflammatory signs and symptoms of rheumatoid arthritis [79]. CDAI, Clinical Disease Activity Index; CRP, C-reactive protein.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2483438&req=5

Figure 3: Threshold hypothesis of osteoclast activation. (a) Osteoclast activation is assumed to occur only after passing a putative threshold. (b) Anti-TNF therapy may ideally lead to total inhibition of bioactive TNF. (c) In other patients, anti-TNF therapy may reduce TNF activity below the threshold of osteoclast activation; these patients may continue having signs and symptoms of rheumatoid arthritis. (d) In yet another group of patients, the TNF activity may be reduced, but not to a level that goes below the threshold of osteoclast activation; in these patients, there will be more inflammation than in (c) and some residual destruction – in relation to other therapies, such as methotrexate, the destruction will be significantly less at a similar level of inflammatory signs and symptoms of rheumatoid arthritis [79]. CDAI, Clinical Disease Activity Index; CRP, C-reactive protein.
Mentions: In this context it needs to be borne in mind that TNF and IL-6 are cytokines that promote osteoclast differentiation and activation [20,21,74-77]. Importantly, under stable low concentrations of RANKL, increasing amounts of proinflammatory cytokines, such as TNF, will lead to increasing osteoclast differentiation [78]. It is therefore conceivable that this relation of TNF levels and osteoclast activation also exists in vivo. In support of this notion, treatment of RA patients with a TNF inhibitor plus methotrexate leads to a dissociation of the close relationship between joint damage and the inflammatory response (exemplified by disease activity measures) [79], and these data were meanwhile confirmed with another TNF-blocker [80]. These findings have led to the threshold hypothesis shown in Figure 3. According to this hypothesis, TNF will lead to joint damage especially once its levels exceed a particular threshold that lies above the threshold needed for the activation of the inflammatory response. Blocking of TNF may inhibit its bioactivity fully (Figure 3b), may reduce bioactivity to levels below the putative threshold of destruction with residual signs and symptoms but no destruction (Figure 3c), or may reduce bioactivity to levels above that threshold but still significantly retard joint damage compared with other treatment modalities, without preventing progression in full (Figure 3d). This hypothesis is in line with results from clinical trials where the use of TNF inhibitors significantly retarded or halted joint destruction despite residual active disease [81-83].

Bottom Line: It will be shown that the relationship of many biomarkers with disease characteristics is confounded by factors unrelated to the disease, and that only few biomarkers exist with some predictive value.Moreover, clinical markers appear of equal value as biomarkers for this purpose, although they likewise have limited capacity in these regards.The analysis suggests the search for better markers to predict outcomes and therapeutic responsiveness in rheumatoid arthritis needs to be intensified.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. josef.smolen@meduniwien.ac.at

ABSTRACT
Rheumatoid arthritis is a heterogeneous disease with respect to clinical manifestations, serologic abnormalities, joint damage and functional impairment. Predicting outcome in a reliable way to allow for strategic therapeutic decision-making as well as for prediction of the response to the various therapeutic modalities available today, especially biological agents, would provide means for optimization of care. In the present article, the current information on biological and clinical markers related to disease activity and joint damage as well as for predictive purposes is reviewed. It will be shown that the relationship of many biomarkers with disease characteristics is confounded by factors unrelated to the disease, and that only few biomarkers exist with some predictive value. Moreover, clinical markers appear of equal value as biomarkers for this purpose, although they likewise have limited capacity in these regards. The analysis suggests the search for better markers to predict outcomes and therapeutic responsiveness in rheumatoid arthritis needs to be intensified.

Show MeSH
Related in: MedlinePlus