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 Novel Baseline Biomarker of Acute-Phase Serum Amyloid A (A-SAA) and Serum Interleukin2 Receptor alpha (sIL-2R) Predicted Long-Term (18 to 35 Yrs) Mortality of Incident Rheumatoid Arthritis (RA) and Matched Non-RA Cohort Controls (CN).

Masi2,  Alfonse T., Aldag2,  Jean C., Sipe1,  Jean D.

Center for Scientific Review, NIH, Bethesda, MD
University of Illinois College of Medicine at Peoria, Peoria, IL

Purpose:

Research on biomarkers of mortality has high priority, especially for cardiovascular causes. Serum markers have predicted such mortality but not over decades-long intervals. This prospective study aimed to identify baseline, long-term biomarker predictors of mortality outcomes of incident RA and matched non-RA cohort CN.

Design:

In 1974, 54 subjects had enrolled into a community-based cohort (n = 21,061 adults) who later had onset of ACR-positive RA, after 3 to 20 (mean 12) years (1977 – 1994). Each RA case was matched by age, gender, and race (all Caucasian) at baseline with 4 cohort non-RA CN. Baseline stored (-70°C) sera were assayed (ELISA) blindly for biomarkers. High sensitivity CRP (hsCRP) and A-SAA were assayed (Hemagen kits) at Boston University (sensitivity 0.1 mg/ml for hsCRP and 1 mg/ml for A-SAA). Three cytokines (IL-1b, IL-6, and TNF-a) and 3 cytokine receptors/antagonists (sIL-2Ra, sTNF-R1, and IL-1ra) were assayed (R & D Systems, high sensitivity kits) at Specialty Laboratories, Santa Monica, CA. Two baseline (1974) biomarkers correlated with mortality of all subjects from 1992–2009, i.e., A-SAA, p = 0.001 and sIL-2Ra (CD25), p = 0.036 (but not CRP, p = 0.125). Sex- and age-specific upper quartile values of A-SAA and sIL-2Ra were determined and a gradient score of their combined results was formulated: 1 = all negative tests (single only or both assayed); 2 = one test negative and other positive (or neither test assayed), and 3 = all positive tests (single only or both assayed). All cause, primary cardiovascular (ICD-9, 390–459 & ICD-10, 00–99), and all other combined mortality was monitored from 1992 thru 2009, excluding 12 pre-1992 deaths. Percentages of deaths by the biomarker gradient were determined. Hazard ratios (HR) of the biomarker gradient for mortality were estimated by Cox regression models.

Results:

Deaths from all causes occurred in 27 (50%) of 54 RA vs 63 (31%) of 204 non-RA, OR = 2.24, 95% CI 1.22 – 4.12, p = 0.010. For all causes, HRs of the biomarker gradient were significant for deaths in RA (p = 0.026), non-RA (p = 0.002), and total (p < 0.001) subjects. For circulatory mortality, HRs of the biomarker gradient were significant for deaths in total (p < 0.001) and non-RA (p = 0.001) subjects, and nearly in RA (p = 0.072). For non-circulatory deaths, the biomarker only weakly predicted deaths in total subjects, p = 0.049 (Table 1):

Causes of Deaths and the Biomarker GradientRheumatoid Arthritis (N=54) N (%) of DeathsNon-Rheumatoid Arthritis (N=204) N (%) of DeathsTotal Cohort Subjects (N=258) N (%) of Deaths
All Causes of Deaths:   
Negative Only8 (34.8%) of 2322 (22.2%) of 9930 (24.6%) of 122
No Assays or Neg & Pos13 (56.5%) of 2331 (36.0%) of 8644 (40.4%) of 109
Positive Only6 (75.0%) of 810 (52.6%) of 1916 (59.3%) of 27
Total Mortality27 (50.0%) of 5463 (30.9%) of 20490 (34.9%) of 258
Cox Regression Model: HR (95% CI) of Biomarker Gradient for Mortality (p Values)1.80 (1.07–3.03) (p = 0.026)1.78 (1.24–2.55) (p = 0.002)1.83 (1.36–2.46) (p < 0.001)
Circulatory Deaths:   
Negative Only1 (4.3%) of 236 (6.1%) of 997 (5.7%) of 122
No Assays or Neg & Pos4 (17.4%) of 2314 (16.3%) of 8618 (16.5%) of 109
Positive Only2 (25.0%) of 86 (31.6%) of 198 (29.6%) of 27
Total Mortality7 (13.0%) of 5426 (12.7%) of 20433 (12.8%) of 258
Cox Regression Model: HR (95% CI) of Biomarker Gradient for Mortality (p Values)2.57 (0.92–7.19) (p = 0.072)2.62 (1.51–4.54) (p = 0.001)2.62 (1.61–4.25) (p < 0.001)
Non-Circulatory Deaths:   
Negative Only7 (30.4%) of 2316 (16.2%) of 9923 (19.9%) of 122
No Assays or Neg & Pos9 (39.1%) of 2317 (19.8%) of 8626 (23.9%) of 109
Positive Only4 (50.0%) of 84 (21.1%) of 198 (29.6%) of 27
Total Mortality20 (37.0%) of 5437 (18.1%) of 20457 (22.1%) of 258
Cox Regression Model: HR (95% CI) of Biomarker Gradient for Mortality (p Values)1.59 (0.87–2.92) (p = 0.134)1.33 (0.82–2.17) (p = 0.253)1.47 (1.00–2.16) (p = 0.049)

Conclusions:

Baseline (1974) upper quartile values of serum A-SAA and sIL-2Ra predicted long-term (18 to 35 yrs) mortality (p < 0.001), mainly attributable to circulatory (p < 0.001), than other (p = 0.049), causes of death. This novel biomarker deserves further testing as a long-term predictor of cardiovascular mortality.

To cite this abstract, please use the following information:
Masi, Alfonse T., Aldag, Jean C., Sipe, Jean D.; A Novel Baseline Biomarker of Acute-Phase Serum Amyloid A (A-SAA) and Serum Interleukin2 Receptor alpha (sIL-2R) Predicted Long-Term (18 to 35 Yrs) Mortality of Incident Rheumatoid Arthritis (RA) and Matched Non-RA Cohort Controls (CN). [abstract]. Arthritis Rheum 2010;62 Suppl 10 :49
DOI: 10.1002/art.27818

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