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In the general population, high-sensitivity C-reactive protein (hsCRP), a marker of inflammation, is a predictor of coronary artery disease (CAD) (1). Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease with a markedly increased risk of CAD (2). While in healthy subjects, levels of hsCRP are relatively stable over time, in patients with SLE, hsCRP takes a dynamic course, and levels fluctuate due to changes in disease activity, treatment, and infections (3, 4). This variability of hsCRP has cast doubt over its usefulness as a predictor of CAD in SLE.

In a prospective cohort study, we observed patients at the University of Toronto lupus clinic for the occurrence of incident CAD events (myocardial infarction [MI] and angina). Consent was obtained from all study participants. Levels of hsCRP (mg/liter) were measured in serum samples collected at baseline and at every visit during the study. The time-adjusted mean of all hsCRP measurements from each patient was calculated as the area under the curve of hsCRP against time, divided by the time from first to last measurement. Cumulative disease activity at each visit coinciding with hsCRP measurement was quantified using the adjusted mean Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) (5, 6).

Among 472 study participants, 89% were women, with a median SLEDAI-2K score and a median Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (7) score at first hsCRP measurement of 4.0 and 1.0, respectively. Mean ± SD disease duration at baseline was 13.8 ± 10.1 years. Analyses were based on a mean ± SD of 5.3 ± 2.5 serial hsCRP measurements per patient (2,523 hsCRP measurements in total). The time interval between hsCRP measurements was 1.3 ± 0.7 years.

Over a mean ± SD followup period of 3.8 ± 5.4 years (2,535.70 person-years in total), 20 new CAD events (8 MI, 12 angina, 0 sudden cardiac death) occurred. In univariate analyses, patients who experienced CAD events were more likely to be older (mean ± SD 47.6 ± 13.0 versus 41.4 ± 14.1 years; P = 0.047) and menopausal (62.5% versus 36.9%; P = 0.04) at study entry. Patients with CAD events had significantly higher 10-year Framingham Risk Scores at study entry (5.40 ± 5.17 versus 2.52 ± 3.67; P = 0.001) (8).

Results of multivariable regression analyses for CAD events are presented in Table 1. Mean and time-adjusted mean hsCRP were significantly predictive of CAD events. At each visit, higher hsCRP quartiles (as defined for the general population based on relative risk of CAD at 5 years) (9) were associated with a significantly increased likelihood of CAD events at subsequent visits (Table 1), with a level of ≥1.6 mg/liter denoting patients at substantially increased risk of CAD (hazard ratio 3.37 [95% confidence interval 1.09–10.41], P = 0.04). In each of these models, the Framingham Risk Score and adjusted mean SLEDAI-2K score were also significantly predictive of CAD events.

Table 1. Time-dependent proportional hazards regression analysis for coronary artery disease events with various measures of hsCRP*
VariableTime-dependent covariate model
Mean hsCRPTime-adjusted mean hsCRPhsCRP quartiles
HR (95% CI)PHR (95% CI)PHR (95% CI)P
  • *

    Hazard ratios (HRs) and 95% confidence intervals (95% CIs) are based on the likelihood of developing a coronary artery disease event with each unit increase in mean high-sensitivity C-reactive protein (hsCRP) (log10 transformed; original units mg/liter), time-adjusted hsCRP (log10 transformed; original units mg/liter), or hsCRP quartile in relation to each unit increase in the Framingham Risk Score and adjusted mean Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K).

  • Defined as hsCRP quartiles of <0.8 mg/liter, 0.8 to <1.6 mg/liter, 1.6 to 3.5 mg/liter, and >3.5 mg/liter.

  • Reported in the same units as the SLEDAI 2000.

hsCRP1.58 (1.05–2.39)0.031.61 (1.06–2.43)0.031.57 (1.02–2.43)0.04
Framingham Risk Score1.15 (1.06–1.26)0.0021.15 (1.05–1.26)0.0021.15 (1.05–1.27)0.0025
Adjusted mean SLEDAI-2K1.13 (1.04–1.24)0.0061.13 (1.04–1.24)0.0061.12 (1.02–1.22)0.013

A limitation of this study is that we were unable to evaluate the role of other cardiovascular risk factors such as obesity, physical inactivity, and metabolic syndrome. However, our findings have potential implications for clinical practice, making a case for measuring hsCRP in patients with SLE in order to identify those most likely to develop clinical CAD. Further studies are needed to confirm our findings and provide recommendations for management of elevated hsCRP levels in SLE.

Acknowledgements

  1. Top of page
  2. Acknowledgements
  3. REFERENCES

Supported by the Centre for Prognosis Studies in the Rheumatic Diseases, the Smythe Foundation, the Ontario Lupus Association, the Lupus Flare Foundation, and the Lupus Society of Alberta. Dr. Nikpour's work was supported by the Arthritis Centre of Excellence and the Geoff Carr Lupus Fellowship.

REFERENCES

  1. Top of page
  2. Acknowledgements
  3. REFERENCES
  • 1
    Ridker PM, Bassuk SS, Toth PP. C-reactive protein and risk of cardiovascular disease: evidence and clinical application. Curr Atheroscler Rep 2003; 5: 3419.
  • 2
    Urowitz MB, Bookman AA, Koehler BE, Gordon DA, Smythe HA, Ogryzlo MA. The bimodal mortality pattern of systemic lupus erythematosus. Am J Med 1976; 60: 2215.
  • 3
    Nikpour M, Gladman DD, Ibanez D, Urowitz MB. Variability and correlates of high sensitivity C-reactive protein in systemic lupus erythematosus. Lupus 2009; 18: 96673.
  • 4
    Ockene IS, Matthews CE, Rifai N, Ridker PM, Reed G, Stanek E. Variability and classification accuracy of serial high-sensitivity C-reactive protein measurements in healthy adults. Clin Chem 2001; 47: 44450.
  • 5
    Gladman DD, Ibanez D, Urowitz MB: Systemic Lupus Erythematosus Disease Activity Index 2000. J Rheumatol 2002; 29: 28891.
  • 6
    Ibanez D, Urowitz MB, Gladman DD. Summarizing disease features over time. I. Adjusted mean SLEDAI derivation and application to an index of disease activity in lupus. J Rheumatol 2003; 30: 197782.
  • 7
    Gladman DD, Urowitz MB, Goldsmith CH, Fortin P, Ginzler E, Gordon C, et al. The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in patients with systemic lupus erythematosus. Arthritis Rheum 1997; 40: 80913.
  • 8
    Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: 183747.
  • 9
    Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998; 98: 7313.