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.
A Signature of Aberrant Responsiveness of the Peripheral Immune System Predicts the 6-Month Risk of Infections in Rheumatoid Arthritis.
L. Krause, Megan, M. Davis III, John, A. Strausbauch, Michael, S. Crowson, Cynthia, M. Therneau, Terry, L. Matteson, Eric, L. Knutson, Keith
Patients with rheumatoid arthritis (RA) experience a high burden of infectious disease, which is a leading cause of mortality. Currently there are no biomarkers that stratify the risk of infections in these patients. We have recently shown that "signatures" of aberrant functional responsiveness of the peripheral immune system are associated with RA disease severity. We performed a pilot study to assess whether a blood-based immune signature could predict incident infections in patients with RA.
We designed a prospective, population-based cohort study of patients with RA. Infections were identified first by diagnosis codes and then validated by medical records review using previously published definitions. Peripheral blood mononuclear cells were isolated and stimulated with a panel of stimuli for both the innate and adaptive immune systems. Seventeen cytokine concentrations were measured via multiplex immunoassays. The stimulation panel included anti-CD3/anti-CD28, cytomegalovirus and Epstein Barr virus lysates, CpG oligonucleotides, heat shock protein 60, phytohemagglutinin, phorbol myristate acetate with ionomycin, and Staphylococcal enterotoxins A and B. Mixed models were used to normalize log-transformed cytokine concentrations, adjust for assay effects, and to estimate and test for differences between the groups with and without incident infections. An immune signature score was created by selecting cytokine-stimulation combinations that were significantly different (p<0.05) between the groups. Logistic regression was used to test the association of a multi-cytokine prediction score and the risk of incident infections.
In the six-month period following the index blood draw, 28 incident infections occurred among 267 patients with RA, 74.5% female, with mean age of 61 years and mean disease duration of 9.6 years. The only statistically significant variable at baseline that predicted infection was functional status defined by the Health Assessment Questionnaire (HAQ) disability index. Nine cytokine-stimulation combinations were significantly different between those with and without infection, including higher levels of TNFa, IFNg, IL-17, IL-8, and GM-CSF and lower levels of IL-10 and IL-12 in response to various stimuli. The immune signature score was a statistically significant determinant of the 6-month risk of infections with an odds ratio of 4.0 (95% CI: 1.5 to 11, P=0.007) after adjusting for age, gender, HAQ, and use of disease-modifying medications.
This was one of the first studies to analyze ex vivo cytokine production and derive an immune signature that could help predict infection risk in patients with RA. The ability to predict infection risk could affect the choice of RA medications with their inherent immunosuppressive effects and the use of antibiotic prophylaxis. Reducing infection by preemptively altering therapy based on infection risk would have the potential to reduce morbidity and mortality for patients with RA.
To cite this abstract, please use the following information:
L. Krause, Megan, M. Davis III, John, A. Strausbauch, Michael, S. Crowson, Cynthia, M. Therneau, Terry, L. Matteson, Eric, et al; A Signature of Aberrant Responsiveness of the Peripheral Immune System Predicts the 6-Month Risk of Infections in Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2216