Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Quality and duration of response to rituximab in rheumatoid arthritis have not been completely explained. In the synovium, three studies have indicated a relationship between higher plasma cell numbers at baseline and worse, or shorter lasting responses1,2,3. In this study we measured synovial expression of genes involved in B-cell biology, cell survival and trafficking and inflammation.
Methods:
Synovial arthroscopic biopsies were collected and snap frozen from patients at baseline and 26 weeks after rituximab . Immunohistochemistry was performed for CD3, CD19, CD20cy, CD138 and CD68 using the Menarini universal staining kit and scored for positive cells/mm2 using digital image analysis. The remainder of the tissue was used for RNA extraction. A 48 gene custom Taqman array was designed, including cell lineage markers (CD19, CD20, CD3, CD138, CD68), genes of the BAFF-APRIL system, immunoglobulins, cytokines, chemokines and adhesion molecules implicated in RA synovitis or cell trafficking, and a reference gene (HPRT). Informative data are available from 32 biopsies before and 23 post treatment.
Results:
As previously reported, IHC showed complete B-cell depletion in synovium in 22/25 patients using both CD19 and CD20cy antibodies.
Plasma cells (CD138) were not significantly reduced and post-treatment. CD138 IHC-score was lower in patients with sustained clinical response (>12 months), and these patients also had significantly lower post-treatment rheumatoid factor titre. CD138 IHC score correlated with baseline CXCL13 (R=0.738, p<0.001), and negatively with baseline EGF (R=-0.617, p=0.006). Post-treatment plasma cell IHC-score also correlated significantly with immunoglobulin kappa and heavy constant chain gene expression, but none of the immunoglobulin genes was significantly associated with sustained response.
Comparing EULAR responders and non-responders, there were trends to higher baseline CD20 gene expression in non-responders (p=0.079) and greater reduction in CXCL13 (p=0.066) and MMP (p=0.024) in responders.
Lower expression of ICAM (p=0.021), FGF (p=0.044), CD20 (p=0.055) and p53 (p=0.025) and higher expression of APRIL (p=0.029) at baseline was associated with normalisation of CRP after therapy. Furthermore, these patients also showed a significantly greater reduction in expression of CD4, CD55, CD68, CXCL12, EGF, FGF, ICAM, PECAM, STAT5, TGF-beta, APRIL and BAFF (all p<0.05).
Conclusion:
Preliminary results indicate important differences in synovial gene expression in patients with clinical response to rituximab, notably in relation with genes involved in cell trafficking and survival.These results may help elucidating reasons for, and consequences of plasma cell survival.
References
1. Teng et al. A&R (2008) 56(12)
2. Thurlings et al. ARD (2008) 67
3. Vital et al. EULAR 2012
Disclosure:
Y. El-Sherbiny,
None;
S. Churchman,
None;
F. Ponchel,
None;
P. Emery,
None,
;
E. M. Vital,
Roche Pharmaceuticals,
2,
Roche Pharmaceuticals,
8.
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