Tocilizumab and rituximab, but not adalimumab, display highly concordant molecular effects in the rheumatoid arthritis synovium

Objectives: The clinical effects of biologics in patients with rheumatoid arthritis (RA) are well known. By contrast, little is known about their molecular effects in the RA synovium, and how the administration of these agents can be tailored according to individual disease status. Here, we compared the effects of three biologics on global synovial gene expression profiles in RA patients. Methods: Previously reported high-density transcriptomic data (GeneChip HGU133 Plus 2.0 slides) were recovered, obtained in our laboratory using synovial biopsies from patients with osteoarthritis (OA, n=5), early untreated RA (n=7), Methotrexate-resistant RA patients before and 3 months after Adalimumab therapy (n=2x8), anti-TNF resistant RA patients before and 3 months after Rituximab therapy (n=2x12). In addition, new hybridizations were performed with synovial biopsies from untreated early RA patients before and 3 months following Tocilizumab therapy (n=2x12) Results: Comparison of RA and OA synovial biopsies led to the identification of 885 RA specific probe sets (535 are up-regulated and 350 are down-regulated in RA synovial tissue). Most (88%) of the probe sets up-regulated in the early RA synovium are down-regulated by Tocilizumab and Rituximab in their respective patients' populations; conversely, 60% of the transcripts down-regulated in RA synovial tissue are up-regulated by both therapies. Changes in gene expression induced by Tocilizumab and Rituximab are highly correlated (r = 0.5797, p < 0.0001); by contrast, much less similarities are found when Tocilizumab or Rituximab is compared to Adalimumab. When the same analyses are applied on all probe sets expressed in the synovium, the same similarities between Tocilizumab and Rituximab are found (r = 0.4116, p < 0.0001), while the effects of Adalimumab appear to be different. Conclusion: The concordance between the molecular effects of Rituximab and Tocilizumab suggests that IL-6 producing- and B cells are major players in the physiopathology of the disease. Adalimumab admisnistration is associated with different patterns of molecular changes in the RA synovium. These data contribute to a better knowledge of the synovial molecular effects of therapies and open perspectives for the individualization of therapeutic decisions