Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


The HLA Haplotype DQA1, DQB1, DR4- Identifies Lupus Patients in Whom Anti-dsDNA Titers Correlate with Disease Activity.

Olferiev1,  Mikhail, Kirou1,  Kyriakos A., Lundsgaard4,  Dorthe, Frederiksen3,  Klaus S., Fleckner2,  Jan, Crow1,  Mary K.

Hospital for Special Surgery, New York, NY
Novo Nordisk
Novo Nordisk, Denmark
Novo Nordisk, Copenhagen, Denmark

Objective:

Anti-dsDNA titers are used by rheumatologists to assist in disease activity assessment of SLE patients. However, anti-dsDNA titers do not always correlate with disease activity. In this study we explored whether SLE patients with anti-dsDNA titers that parallel disease activity [based on SELENA SLEDAI (SS) score] differ in their PBMC transcriptional profile compared to other SLE patients.

Methods:

Longitudinal PBMC and plasma samples were obtained over an average 6 visits (2–12) from 23 SLE patients and 5 healthy donors (HD). The duration of study follow-up for individual patients varied from 197 to 812 days. Plasma levels of autoantibodies were evaluated using the Multi-Analyte Profiling (MAP) technology (Rules-Based Medicine, Austin, TX). PBMC transcriptional profiles for each visit were established using Human Genome U133 Plus 2.0 Arrays.

Results:

Microarray data analysis revealed 566 differentially expressed transcripts comparing HD samples versus samples of SLE patients during mild/moderate or severe SELENA SLEDAI flares, or those without a flare (ANOVA FC<2.0, p<0.05). From 44 tested autoantibodies 14 were significantly upregulated in SLE patients (T TEST and fold change (FC) = p<0.05 and >1.5). Eight autoantibodies, including anti-dsDNA, correlated weakly with disease activity based on SS. Nine patients showed high levels of anti-dsDNA autoantibody. Comparative analysis of transcripts between anti-dsDNA positive and negative patients identified 136 differentially regulated transcripts (FC>1.5 and p<0.05). Comparative analysis of those transcripts and autoantibody titer showed that anti-dsDNA autoantibodies correlated with multiple interferon signature genes and granulocyte markers (LTF, CEACAM6, MPO, and MMP9). Five SLE patients (22%) showed a strong correlation of anti-dsDNA titer and SS score (R=0.9; p<0.001). Comparative analysis of transcripts in those individuals compared with the other lupus patients identified 38 transcripts (FC>1.5; p<0.05). Of interest, the anti-dsDNA patients were all positive for HLA alleles DQA1, DQB1 and negative for DR4, in contrast to variable alleles for the rest of the patients (Fisher's test p<0.01).

Conclusion:

SLE patients showing strong correlation of anti-dsDNA titers and disease activity have a distinct MHC class II haplotype. This observation, if confirmed, may help to identify SLE patients in whom anti-dsDNA titers are helpful in management of disease. This genetic background may favor skewing of the autoimmune response toward certain dsDNA epitopes that are particularly pathogenic.

To cite this abstract, please use the following information:
Olferiev, Mikhail, Kirou, Kyriakos A., Lundsgaard, Dorthe, Frederiksen, Klaus S., Fleckner, Jan, Crow, Mary K.; The HLA Haplotype DQA1, DQB1, DR4- Identifies Lupus Patients in Whom Anti-dsDNA Titers Correlate with Disease Activity. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :508
DOI: 10.1002/art.28277

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