Relationships Between a Serum Biomarker of B Cell Differentiation and B Cell Activating Factor Suggest Possible Distinct Pathways of Response to Rituximab in Patients with Systemic Lupus Erythematosus

Ricardo Marques¹, Laura Heretiu², David A. Isenberg³, Maria J. Leandro³ and Geraldine Cambridge³, ¹Serviço de Medicina Interna B, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal, ²Medicine, Centre for Rheumatology, Division of Medicine, University College London, London, United Kingdom, ³Centre for Rheumatology, Division of Medicine, University College London, London, United Kingdom

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: B cell targeting, biomarkers and rituximab, SLE

Session Information

Date: Tuesday, November 15, 2016

Title: Systemic Lupus Erythematosus – Clinical Aspects and Treatment IV: Biomarkers

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Rituximab (RTX) has been used off-label in refractory SLE with variable clinical outcomes in different cohorts, with no predictive response markers available. However, the kinetics suggest that interruption of B cell maturation and differentiation, rather than removal of B cells per se, may underlie clinical success. The soluble form of CD23 (sCD23) is cleaved and released during B cell differentiation to memory phenotype (CD27+). Concerted binding of B cell activation factor (BAFF) to at least 3 receptors is a survival factor for naïve B cells, promotes class-switch and plasmablast differentiation. We aimed to investigate whether different sCD23 and BAFF profiles could be of value for predicting clinical response to RTX in patients with SLE.

Methods: We included 98 serum samples from 26 SLE patients (ACR 1982 revised criteria) taken 3 to 13 months prior to first RTX treatment. BAFF and sCD23 were determined using ELISA [upper limits of normal (ULN) given by manufacturers: sCD23 >5000pg/ml; BAFF >2ng/ml]. Data was analyzed in relation to B cell depletion (CD19+B cells<5/μl), clinical characteristics, anti-dsDNA and BILAG response at 6 months.

Results: Table 1 shows clinical data and results. Serum sCD23 and BAFF were weakly correlated in all samples (r²=0.11; p=0.001). Levels of both analytes from individual patients were found to follow broadly consistent patterns. Patients could therefore be grouped according to levels greater or lower than ULN: Group I – High sCD23, Low BAFF; Group II – High sCD23, High BAFF; Group III – Low sCD23, Low BAFF; Group IV – Low sCD23, High BAFF. Patients in Groups I and IV had higher BILAG responses at 6 months. No patients in Group III had renal involvement.

Table 1.
	Group I High sCD23, Low BAFF n=5	Group II High sCD23, High BAFF n=8	Group III Low sCD23, Low BAFF n=6	Group IV Low sCD23, High BAFF n=7	Total n=26

Ethnicity
Caucasian	5 (100%)	3 (37.5%)	3 (50%)	3 (42.9%)	14 (53.8%)
Afro-Caribbean	0 (0%)	5 (62.5%)	2 (33.3%)	4 (57.1%)	11 (42.3%)
Asian	0 (0%)	0 (0%)	1 (16.7%)	0 (0%)	1 (3.8%)

Auto-antibodies
dsDNA +	3 (60%)	7 (87.5%)	5 (83.3%)	5 (71.4%)	20 (76.9%)

Clinical Involvement
Renal	2 (40%)	4 (50%)	0 (0%)	4 (57.1%)	10 (38.5%)
Neurological	0 (0%)	0 (0%)	1 (16.7%)	2 (28.6%)	3 (11.5%)
Fatigue	2 (40%)	6 (75%)	5 (83.3%)	2 (28.6%)	15 (57.7%)

Clinical Response
3M Depletion	4 (80%)	3 (50%) 2 missing values	4 (66.7%)	4 (57.1%)	15 (62.5%) 2 missing values

6M BILAG Response
Complete/Partial	4 (80%)	2 (25%)	2 (33.3%)	5 (71.4%)	11 (42.3%)
No	1 (20%)	6 (75%)	4 (66.7%)	2 (28.6%)	12 (46.2%)
M – Months; Depletion defined as less than 5 CD19+ B cells/μl

Discussion: Group I: High sCD23: increased differentiation of naïve to memory B cells, together with a good response to RTX, suggest T cell stimulation is driving the process in a BAFF independent fashion. Group II: Poor depletion and high sCD23 suggests stimulation/maturation of post-germinal center B cells, with possible BAFF-driven differentiation to memory B cells and antibody producing B cells. B cell resistant to RTX-depletion in protected sites may explain poor clinical responses. Group III: Low sCD23 and BAFF suggests that B cells may not be central in the pathogenesis, with a more T cell dependent process. This could explain the poorer clinical response to RTX despite good depletion. Group IV: High BAFF stimulates autoreactive naïve B cell differentiation directly to plasmablasts and autoantibody production, bypassing memory B cells (Low sCD23). Resulting immune-complexes processed through antigen presenting cells (and IFN signature) continuously stimulate BAFF production.

Conclusion: Based on the patterns of sCD23 and BAFF and B cell biology observed in SLE we hypothesize that the combination of these biomarkers may identify distinct autoimmune pathways and likely predict clinical response.

Disclosure: R. Marques, None; L. Heretiu, None; D. A. Isenberg, None; M. J. Leandro, Roche Glycart, 2,Genentech and Biogen IDEC Inc., 9,Roche Pharmaceuticals, 9; G. Cambridge, None.

To cite this abstract in AMA style:

Marques R, Heretiu L, Isenberg DA, Leandro MJ, Cambridge G. Relationships Between a Serum Biomarker of B Cell Differentiation and B Cell Activating Factor Suggest Possible Distinct Pathways of Response to Rituximab in Patients with Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/relationships-between-a-serum-biomarker-of-b-cell-differentiation-and-b-cell-activating-factor-suggest-possible-distinct-pathways-of-response-to-rituximab-in-patients-with-systemic-lupus-erythematosus/. Accessed .

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