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 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 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= 2 x 8), anti-TNF-resistant RA patients before and 3 months after Rituximab therapy (n= 2 x 12). In addition, new hybridizations were performed with synovial biopsies from untreated early RA patients before and 3 months following Tocilizumab therapy (n= 2 x 12).
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.
7 out of 12 early RA patients treated with Tocilizumab were in SDAI remission 6 months after initiation of therapy. Patients who did not reach remission had higher baseline expression of IL-6 induced transcripts, including immunoglobulin genes. By contrast, expression of immunoglobulin genes is higher in RA patients who respond to Rituximab therapy.
Conclusions Genes differentially expressed in early RA versus OA synovial biopsies are IL-6 and B-cell dependent. The concordance between the molecular effects of Rituximab and Tocilizumab suggests that IL-6 producing B cells are major players in the physiopathology of the disease. Tocilizumab therapy could be less efficient in patients displaying a very strong synovial IL-6 signature. Our results suggest that administration of Rituximab could bypass this obstacle in such patients. Further studies are needed to confirm whether therapy can be tailored according to the molecular patterns found in individual patients.
Disclosure of Interest None Declared
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