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.
An Immune Signature Based on Ex Vivo Responsiveness of Peripheral Blood Cells Is Associated with Radiographic Joint Damage in Rheumatoid Arthritis.
M. Davis III, John, L. Knutson, Keith, A. Strausbauch, Michael, S. Crowson, Cynthia, M. Therneau, Terry, L. Matteson, Eric, E. Gabriel, Sherine
In rheumatoid arthritis (RA), joint damage may occur even in patients with minimal disease activity. Thus, new techniques for determining the potential for future immune-mediated joint injury may facilitate targeting high-risk patients for aggressive therapy. The objective was to identify immune signatures of RA damage by broadly assessing ex vivo cytokine release by PBMC in response to stimulation.
We studied patients with early RA of <3 yrs duration, positive for rheumatoid factor or anti-citrullinated peptide antibodies. Radiography of the hands, wrists and feet was performed, and modified van der Heijde-Sharp (vdH-S) scores were determined. To establish immune signatures, we measured the release of 17 cytokines from PBMC in response to a panel of stimuli or in media alone using multiplexed immunoassays. The stimulation panel included anti-CD3/anti-CD28, CpG oligonucleotides (CpG), combined cytomegalovirus and Epstein Barr virus lysates (CMV/EBV), heat shock protein 60 (HSP60), phorbol myristate acetate with ionomycin (PMA/ionomycin), phytohemagglutinin (PHA), and combined Staphylococcal enterotoxins A and B (SEA/SEB). Mixed effects models were used to normalize the cytokine data and adjust for assay effects. Gradient boosting models (GBM) were used to predict the vdH-S score using all of the 136 stimulated cytokine concentrations and thereby derive a multi-cytokine prediction score (scale 0100). Logistic regression models were used to determine the association of the GBM prediction score with the vdH-S score, dichotomized at the median, adjusting for clinical covariates.
The study included 59 patients (median age: 54 yrs; 59% female; RA duration: 12.4 mo); 49 (84%) and 19 (24%) were taking methotrexate and biologics, respectively. The median vdH-S score was 18 units (interquartile range: 7, 37). In the GBM analysis, the production of the following cytokines (by descending relative influence for each stimulant) was associated with the vdH-S score, including: IL-12, IL-1b, and GM-CSF with CMV/EBV; IL-12, IL-10 and IL-4 with PMA/ionomycin; IL-6, IFN-g, and GM-CSF with anti-CD3/anti-CD28; IL-5, IL-12, and IL-10 with SEA/SEB; IL-12 with HSP60; IL-2, IL-4, and MCP-1 with CpG; GM-CSF and IL-5 with PHA; and finally, IL-7 and IL-8 in media alone; this model strongly correlated with the vdH-S score (Spearman correlation: 0.87). Cytokine production was generally increased with high vdH-S scores although GM-CSF, IL-2, IL-4 and MCP-1 were decreased under various stimulations. The multi-cytokine prediction score (per 10 units) was strongly associated with the presence of higher joint damage (vdH-S score >=18 units) with an odds ratio of 1.28 (95% confidence interval: 1.11, 1.46; p<0.001) independent of covariates, including the use of methotrexate, biologics, and prednisone.
A PBMC-based immune signature, reflecting aberrant responsiveness of the peripheral innate and adaptive immune systems, is strongly associated with extent of radiographic joint damage in patients with early RA. Further studies are necessary to understand the biological implications of the findings and to define their clinical applicability.
To cite this abstract, please use the following information:
M. Davis III, John, L. Knutson, Keith, A. Strausbauch, Michael, S. Crowson, Cynthia, M. Therneau, Terry, L. Matteson, Eric, et al; An Immune Signature Based on Ex Vivo Responsiveness of Peripheral Blood Cells Is Associated with Radiographic Joint Damage in Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1580