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Abstract Number: 3105

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

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Session Information

Date: Tuesday, November 15, 2016

Session 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 February 27, 2021.
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