ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1644

Mycophenolic Acid and Ribavirin Induces Cytoplasmic Autoimmunogenic Rods and Rings Structures in Vivo

Gerson D Keppeke Sr.1, Eunice Nunes2, Maria Lucia Ferraz3, Sandro F. Perazzio1, Mônica Prado1, Edward K.L. Chan4 and Luis Eduardo C. Andrade5, 1Rheumatology, Escola Paulista de Medicina - Universidade Federal de São Paulo, Sao Paulo, Brazil, 2Gastroenterology Division, Universidade Federal de São Paulo, Sao Paulo, Brazil, 3Gastroenterology Division, Universidade Federal de São Paulo, São Paulo, Brazil, 4Oral Biology, University of Florida, Gainesville, FL, 5Fleury Laboratories, Sao Paulo, Brazil

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: , , ,

Session Information

Title: Systemic Lupus Erythematosus - Clinical Aspects and Treatment: Biomarker, Translational and Nephritis Studies

Session Type: Abstract Submissions (ACR)

Background/Purpose

Autoantibodies to IMPDH2 occur in Hepatitis C patients receiving ribavirin (RBV) & interferon-α (IFN-α). Anti-IMPDH2 antibodies recognize “rods and rings” (RR) cytoplasmic structures in indirect immunofluorescence on HEp-2 cells (IIF-HEp-2). In vitro inhibition of IMPDH2 by RBV or mycophenolic acid (MPA) induces RR formation. We investigate the in vivo formation of RR structures in patients and mice treated with RBV or MPA.

Methods

Sequentially retrieved RBV/IFN-α-treated HCV (n=108) and MPA-treated Systemic Lupus Erythematosus (SLE) patients (n=78) were tested for anti-RR autoantibodies. Peripheral blood mononuclear cells (PBMC) from 18 MPA-treated SLE and 17 RBV/IFN-α-treated HCV patients were analyzed for RR+ PBMC by double-labeling IIF with human anti-RR serum and rabbit anti-IMPDH2 IgG. Cryosections from 3 untreated and 3 RBV-treated (0.4 mg/day; 3 months) BALB/c mice were screened for RR. 

Results

Forty-one (38%) HCV and none of the SLE patients presented anti-RR autoantibody (p<0.0001). In vivo RR formation in PBMC occurred in all RBV/IFN-α-treated HCV (28.2±15.2% RR+ cells) and MPA-treated SLE (22.3±15.1% RR+ cells) patients (p=0.13). The frequency of RR+ PBMC in HCV correlated with the duration of treatment (r=0.55; p=0.01). In SLE there was no correlation with duration of treatment (r=-0.01; p=0.95), time interval from last dose ingested prior to sample collection (r=0.04; p=0.86) and daily dose (r=0.30; p=0.21). RBV-treated mice showed widespread RR structures, with variable proportion of RR+ cells in the several tissues: spleen (21.5%), stomach (57.8%), liver (70.7%), kidney (38.8%), heart (13.3%), brain (56.2%), muscle (23.7%), skin (37.1%). Untreated mice showed RR only in spleen (16.3%) and pancreas (14.9%).

Conclusion

Ribavirin and MPA generate in vivo formation of IMPDH2-rich RR structures in PBMC from HCV and SLE patients, respectively. In addition, RBV-treated mice show widespread formation of RR with variable proportion of RR-positive cell across the several tissues. These findings support further studies for the investigation of the consequences of widespread RR formation in patients receiving chronic treatment with RBV or MPA, as well as the understanding of the role of in vivo RR structures on the generation of anti-IMPDH2 autoantibodies.

Disclosure:

G. D. Keppeke Sr.,
None;

E. Nunes,
None;

M. L. Ferraz,
None;

S. F. Perazzio,
None;

M. Prado,
None;

E. K. L. Chan,
None;

L. E. C. Andrade,
None.

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