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Abstract Number: 1207

Impact of Anti Tumor Necrosis Factor-Alpha Therapy in Rheumatoid Arthritis On Osteoclast Activation and B Cells

Ezinma Ezealah1, Jennifer Hossler1, Jamie Biear1, Christopher A. Cistrone1, Teresa Owen1, Nida Meednu1, Kelly Callahan1, Arumugam Palanichamy1, Ignacio Sanz2, Allen P. Anandarajah1, Ralf G. Thiele1, Darren Tabechian3, R. John Looney1 and Jennifer H. Anolik1, 1Medicine- Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, 2Rheumatology, Emory University, Atlanta, GA, 3Allergy/Immun/Rheumatology, Univ of Rochester Schl of Med, Rochester, NY

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: B cells, osteoclasts, RANK/RANKL pathway, rheumatoid arthritis (RA) and tumor necrosis factor (TNF)

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Session Information

Title: Rheumamtoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose:  Serum receptor activator of NFkB ligand (RANKL) and its natural decoy receptor, osteoprotegerin (OPG), play key roles in osteoclast activation. In a group of patients with active RA, we tested the hypothesis that initiation of TNF blockade would improve osteoclast activation (reflected by the serum OPG:RANKL ratio).  DAS response was correlated with markers of B cell activation and musculoskeletal ultrasound.

Methods: 18 patients with RA failing methotrexate therapy (disease activity score (DAS) > 4.4) were randomized to receive either etanercept or adalimumab as part of a larger NIH sponsored Autoimmunity of Excellence (ACE) study (n=60). Soluble serum RANKL and OPG were measured by ELISA at baseline, 24, and 52 wk (pg/ml). RA disease activity was followed by DAS28 at baseline, 12 and 24 weeks. Peripheral blood (PB) B cells were phenotyped by flow cytometry using the following surface markers: CD19, IgD, CD27, CD24, CD38, CD95, and CD21. High frequency gray scale (GS) and power Doppler (PD) musculoskeletal ultrasound (MSK US) was performed on a subset of subjects (n=8) on the wrists, MCP, and PIP joints of both hands according to EULAR guidelines by a rheumatologist (DT and RT) certified in MSK US at baseline 4, 12, and 24 wk.  GS US and PD US were scored semiquantitatively (on a severity scale from 0-3). 

Results: In the current analysis of the Rochester cohort (n=18), 61% of patients were good DAS responders, 28% moderate responders, and 11% non-responders at 24 weeks.  Good DAS responders had higher baseline RANKL levels than moderate/non-responders (2653 vs. 1218).  Serum RANKL decreased significantly with anti-TNF treatment (2381+3025 at baseline vs. 921+1630 at 52 wk, p=0.03, n=8 longitudinal), as did OPG (150+92 at baseline vs. 82+51 at 52 wk, p=0.01), regardless of DAS response. Interestingly, the OPG:RANKL ratio was very low in these active RA patients (0.76+1.2 compared to historic healthy controls 3.0) and did not change significantly with anti-TNF treatment. On MSK US, the higher the baseline # of GS+ joints the less likely patients were to achieve a good DAS response.  Additionally good DAS responders tended to have a low # of GS+ joints/absent PD on follow-up US (12 and 24 wk) in contrast to moderate/non-responders.  Finally, RA patients at baseline had an expansion of activated memory B cells in the PB (CD95+ on CD27+IgD- memory in RA [n=13] 50.5+19.5% vs. HC [n=14] 29.6+9.5%, p=0.001; also significant for CD95+ on CD27-IgD- memory p<0.0001 and CD21- on CD27+IgD- memory p=0.02). There was a strong negative correlation between OPG:RANKL ratio and B cell activation (R2=-0.62 for correlation with CD95+ on CD27-IgD- memory), suggesting that activated B cells may contribute to RANKL activation.   Longitudinal assessment of B cell subsets in response to anti-TNF is underway. 

Conclusion: In our study, the OPG:RANKL ratio was considerably lower than the ratio reported for control subjects and similar to that observed in patients with multiple myeloma. B cell activation was characteristic of active RA and correlated with RANKL activation.  These results support the notion that OPG:RANKL and B cells have a central role in RA-associated joint destruction.

Supported in part by the University of Rochester ACE U19 AI563262 and P01 AI078907


Disclosure:

E. Ezealah,
None;

J. Hossler,
None;

J. Biear,
None;

C. A. Cistrone,
None;

T. Owen,
None;

N. Meednu,
None;

K. Callahan,
None;

A. Palanichamy,
None;

I. Sanz,
None;

A. P. Anandarajah,
None;

R. G. Thiele,
None;

D. Tabechian,
None;

R. J. Looney,
None;

J. H. Anolik,
None.

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