Good article from Arthritis Research and Therapy.
Many biological markers reflect the ongoing disease process of RA. The markers' correlation to the typical manifestations of RA, the signs and symptoms of active disease, the destruction of joints or the impairment of physical function, however, has been poor for most of them. This may be due to a variety of reasons. First, what we measure in various body fluids may not reflect sufficiently well what is ongoing in the microenvironment of the joint, and the leakage of various molecules into the body fluids may differ among, and within, patients. Second, where biomarkers have important patho-physiological functions, the concentrations measured may not reflect their functional fraction. Third, the pathogenesis of RA may be highly heterogeneous, with different markers being preponderate in different patients. Fourth, pathogenetic mechanisms may even vary within a patient in the course of the disease. Finally, diurnal and genetic variations may change biomarker levels and confound our ability to interpret them – with relatively low levels in one patient being highly pathogenic, while a high level in another patient may mean little for that particular patient's disease.
Importantly, we have focused here on markers that are frequently used to evaluate disease activity, cartilage and bone damage. There is more going on in relation to the immunopathogenic events, however, than mere production of cytokines and the consequences of their activity. For example, certain T-cell subpopulations have shown changes in active RA [91,92]. The application of such markers in practice, however, is limited by the lack of widespread availability of the respective detection techniques. Also, some imaging techniques, such as magnetic resonance imaging and ultrasound, may allow new insights and may contribute interesting information on disease activity or even outcome [93-95].
More information is presently needed, and the search for the best set of biomarkers for assessment and prediction of disease activity, damage and response to therapy as well as efforts to better standardize biomarker assessment must, and will, go on. Appropriate cohorts of patients and appropriate validation procedures will be needed to this end. For the time being it appears too early to recommend the use of these markers in routine practice or as major outcomes in clinical trials. System biologic approaches may provide better insights in the not too distant future [96], but their applicability in routine settings will constitute yet another challenge. Likewise, proteomic approaches employing various methodological means may prove helpful, but at present merely confirm the complexity of the biological interplay we are dealing with in RA [97].
There are two exceptions, however, which make the above summary much less disappointing: acute phase reactants, especially CRP, are highly reliable markers of disease activity and, in the long term, radiographic outcomes; and auto-antibodies, especially rheumatoid factor and autoantibodies to citrullinated proteins, have diagnostic and prognostic value. That these old markers surpass the value of new ones and that some of the old techniques employed for marker determination may be more reliable than new ones sounds inadequate, but nevertheless it is satisfying that such usefulness and validity does exist for at least few molecules.
Equally important, research activities of the past decade have allowed one to obtain clinical assessment tools – the composite disease activity indices, which are not only reliable for assessing the wellbeing of patients with RA during follow up, but are also highly associated with functional and radiological disease outcome. A combination of such tools with a novel approach to biomarker evaluation may therefore allow for optimized understanding and prediction of the fate of the individual RA patient. There is recognition that clinical assessment (measuring and noting the change in index and the disease activity state attained) early in the course of therapy (3 to 6 months after initiation of therapy) allows one to judge longer-term treatment effects and to make rapid changes of therapeutic modalities in the individual patients in whom low disease activity is not achieved. Such a strategy will consequently be associated with lesser costs by avoiding prolonged use of ineffective therapies and will also lead to a better outcome of RA.