Background B-cells are key mediators in RA pathogenesis through the initiation of several pathways that lead to the perturbation of the immune system. Rituximab, an anti-CD20 monoclonal antibody is recommended for use after failure with traditional disease modifying agents and anti-TNF therapy. Despite using peripheral blood B-cells as a marker to ensure depletion, the clinical response to Rituximab remains variable, highlighting an unmet need for further biomarkers of response. Mechanisms that underpin the variation in clinical outcome are yet to be fully elucidated but may relate to distinct differences in cellular infiltrate and target expression within the synovium.
Objectives The aim of this open-labelled pilot study was to test the hypothesis that patients with a B-cell rich versus B-cell poor synovial pathotype have an enhanced response to B-cell depletion following therapy with Rituximab.
Methods Synovial biopsy (Ultrasound guided n=34, arthroscopic n=6) was performed at baseline in 40 patients with active RA (as defined by a DAS-28 score of >5.1) who had failed treatment with standard disease modifying therapy. 35 patients had received prior anti-TNF therapy, a subset of 5 patients were anti-TNF naïve. Rituximab was administered, with appropriate pre-medication, as two intravenous infusions at a dose of 1g 14 days apart. Synovial tissue was fixed in formalin, paraffin-embedded and cut to serial sections (3μm). Histological grading and lymphoid organization of the synovium was assessed by immunohistochemical analysis. After staining for CD20, the presence or absence of B-cells was determined by a semi-quantitative score (0-4)1. CD21 staining was carried out on samples with large aggregates to determine the presence of FDC in germinal centres (GC) within the synovium. Disease response to treatment (improvement in DAS-28>1.2) at 16 weeks was correlated with the presence or absence of B-cells and GC using Fishers exact test and Chi-squared testing, respectively.
Results IHC for CD20 results were available from 39 patients. 29 [74%] patients were females, mean age 58.5 [29-80], 36 [92%] were anti-CCP positive and 32 [82%] were RF positive. 12 [30%] showed a response (DAS-28 >1.2) improvement at 3 months. 24 [62%] patients had little or no B-cell infiltrate within the synovium. In this subgroup, 20 [83%] did not exhibit a significant clinical response. (p=0.031). In B-cell rich non-responders, the presence of GC was noted in 5 out of 6 individuals [83%]; only 1 patient who was GC positive responded to Rituximab. (p=0.01, n=37)
Conclusions This open-labeled pilot study strongly suggests that response to Rituximab therapy is determined by the presence or absence of B-cells within the synovium. In patients with B-cell rich synovium, the presence of GC appears to be an important marker of resistance to Rituximab therapy. This pilot study also highlights the potential to utilize synovial pathotype as a biomarker to predict disease outcomes and response.
Kraan, M.C., Haringman, J.J., Post W.J., Versendaal, J., Breedveld, F.C., Tak. P.P. Immunohistological analysis of synovial tissue for differential diagnosis in early arthritis. Rheumatology 1999; 38:1074–1080.
Disclosure of Interest None declared