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

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.

Figure 1

Triad of rheumatoid arthritis and a selection of markers reflecting its respective elements. The triad of rheumatoid arthritis comprises disease activity–joint damage–disability; a selection of markers that mainly reflect the respective elements of the triad are shown. Over time, the component of disability related to joint destruction will increase and thus disability becomes progressively less reversible; in contrast, with adequate therapy, the component of disability related to disease activity will always be reversible [6,7,98].

Figure 2

Depiction of potential cytokine and cellular patterns in four hypothetical patients with rheumatoid arthritis. Upper panel: hypothetical biological activities of various cytokines. Lower panel: hypothetical biological activities of various cell types. y axis, arbitrary units of activity. For example, in patient #1 TNF does not appear bioactive, while in patient #3 B cells appear uninvolved. Especially in patient #4, however, all cytokines – and in patient #1 all cell types – appear actively engaged in the disease process. In patient #2 IL-6 may not be detectable. It is unclear to what extent which of those cells and/or cytokines is contributing and if one or several targeted therapies would be efficacious. Although such relationships have not yet been elucidated, differences in synovial cellular compositions and cytokine contents have been noted in various studies [55,59,99]. DC, dendritic cells; Fib, fibroblasts.

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.

Figure 4

Time course of disease activity in patients attaining particular disease activity states after 1 year of therapy. Patients who achieved low disease activity or remission at 1 year attained a low disease activity state within 3 to 6 months from the onset of treatment. SDAI, Simplified Disease Activity Index. Reproduced with permission from [87].

Figure 5

Effect of disease-modifying antirheumatic drug therapy. Disease-modifying antirheumatic drugs (DMARDs) will interfere with the disease process at any time point, and will lead to a deflection of the slope of progression from its natural course. The ideal situation would be to diagnose and treat rheumatoid arthritis early; at best, before damage has occurred.