The currently available data from genomics and proteomics studies in RA indicate that the observed molecular heterogeneity in RA mainly reflects differences in immune and inflammation activity (Tab. 1). Gene set analysis revealed differential activation of pathways such as the STAT-1 pathway in synovial tissue and the TGF-p/activin-a in the FLS. The existence of such molecular heterogeneity in RA that may be translated in distinct pathophysiological mechanisms at the site of the lesion would fit a model proposed by Firestein and Zvaifler , who suggested two independent processes in the destruction stage of RA. One is an immune mediated process that might progress to another phase that is centred on autonomous FLS aggression. This model is further supported by data from several animal models where FLS acquire a degree of independence from T-cell control in late destructive disease, implying an autonomous role for stromal elements, responsible for tissue destruction. Hence, both an immune-mediated and a stromal driven form of disease might drive destruction of bone and cartilage. How far this distinction relies on differences in the stage of the disease remains to be established. Clearly, large-scale gene- and protein expression profiling provides a molecular and biological basis for the well recognised but as yet poorly defined heterogeneity of RA.
The challenge now is to understand the biological basis underlying the differential gene expression programs between subgroups of RA patients. This will allow assignment of the biological pathways at play and may ultimately lead to the design of novel treatment modalities for a subgroup of patients. Moreover, we need to integrate the information on differential gene expression and protein patterns in RA with clinical parameters in such a way that it can be applied in a clinical setting to improve patient stratification and the accuracy of treatment decisions. Therefore, studies that provide solid evidence for the clinical relevance of the identified molec ular differences have great priority for the direct future. The assignment of useful and reliable classifiers requires several levels of validation. It is anticipated that the classifying criteria comprise a constellation of biomarkers for use in a multianalyte approach that distinguish different forms or stages of RA. Ultimately, the identification of classifiers would be tremendously important to define homogeneous groups of patients for genetic and clinical studies, aimed to a more personalised therapy.
We are grateful to Drs. Pat Brown and David Botstein, in whose laboratories part of the work described in this report was performed.
Supported in part by the Howard Hughes Medical Institute, EU Marie Curie trainings network EURO-RA, and the Centre for Medical Systems Biology (a centre of excellence approved by the Netherlands Genomics Initiative, and grants from the National Cancer Institute, the Netherlands Organization for Scientific Research (NWO), and the Dutch Arthritis Foundation
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