C-Reactive protein as a lupus biomarker
What is the topic?
C-reactive protein (CRP) is synthesized and released from liver cells as a response to a variety of cellular insults, such as infections and inflammation, and is involved in activation of the complement pathway that is affected in individuals with lupus. CRP levels correlates with disease activity in people with a variety of rheumatic diseases, including rheumatoid arthritis and inflammatory arthritis. However, for reasons that are not clear, CRP levels in individuals with lupus are only modestly elevated. More advanced methods, which allow for the measurement of much smaller quantities of CRP (so-called “high sensitivity CRP,” or hsCRP), could help to further elucidate its role in lupus.
What did the researchers hope to learn?
The researchers hoped to learn about the relationship among hsCRP, lupus disease activity, and the risk of cardiovascular disease in individuals with lupus.
Who was studied?
Adults with lupus who visited the outpatient rheumatology clinics or were admitted to the medical inpatient services at either Ohio State Medical Center (Columbus, OH) or Tuen Mun Hospital (Hong Kong, China) between April and June 2008 were recruited to participate in the study.
Exclusion criteria were as follows: a) patients having confirmed evidence of active infection at the time of blood draw or judged to be infected by the attending physicians (with or without the use of antibiotics or anti-viral agents for treatment); and b) patients having at least 200 µmol/L of creatinine in the blood.
How was the study conducted?
Blood was drawn from each lupus patient in order to measure the following: hsCRP, anti-double-stranded DNA (anti-dsDNA) antibodies, and complement C3 levels.
Lupus disease activity was measured with the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENDA-SLEDAI). Lupus-related organ damage was assessed with the Systemic Lupus International Collaborating Clinics Damage Index (SDI).
Cardiovascular disease risk factors were assessed, including: body mass index (BMI), lipid (fats in the blood) profile, smoking status, presence of diabetes mellitus (blood sugar levels of > 7.0 mmol/L or that required drug therapy) and hypertension (> 140/90 mm Hg on two occasions or when anti-hypertensive drug therapy was initiated).
Advanced statistics were used to determine the relationship among hsCRP, anti-dsDNA levels, complement levels, lupus disease activity, and lupus-related organ damage. Cardiovascular disease risk factors were also compared between patients having differing levels of hsCRP.
What did the researchers find?
The study included 289 individuals with lupus, 94% of which were women. They were, on average, 39 years of age and had lupus for an average of 7.8 years. Almost half of the patients (43%) had organ damage. The patients were taking the following medications (percentage of patients in parentheses): prednisone (73%), hydroxychloroquine (51%), azathioprine (37%), mycophenolate mofetil (8%), cyclophosphamide (3%), calcineurin inhibitors (8%), statins (9%), and angiotensin-converting enzyme inhibitors (29%).
Almost half (42%) of the patients had clinically significant lupus disease activity, which mostly involved the renal (kidney), hematological (blood), musculoskeletal, and dermatological (skin) systems. About 72% of the patients had either elevated anti-dsDNA antibodies or reduced levels of complement.
Only 23% of patients with clinically active lupus did not have detectable levels of hsCRP while 80% of patients who did not have clinically active lupus had undetectable levels of hsCRP. After statistical adjustment for age, sex, BMI, creatinine levels, and medication use, hsCRP levels were significantly correlated with lupus disease activity scores (but not organ damage scores) related to active serositis (inflammation of membranes around internal organs), musculoskeletal disease, and hematological disease. Also, a significant association was found between hsCRP levels and anti-dsDNA antibody levels (but not complement C3 levels).
After statistical adjustment for creatinine levels and lupus disease activity, significantly elevated levels of hsCRP (> 3 mg/L) were found in patients who were male, chronic smokers (> 3 years), had a history of diabetes mellitus requiring treatment, those with a significantly elevated atherogenic index or ratio of total:HDL cholesterol, and those having arterial thrombosis (blood clots in blood vessels). In these patients with significantly elevated levels of hsCRP (> 3 mg/L), hsCRP levels correlated significantly with damage to the lungs and endocrine system (glands).
What were the limitations of the study?
First, hsCRP levels can fluctuate over time due to infections. Second, a “spot” value of hsCRP (as obtained in this study), especially during an infection, may not accurately reflect lupus-related cardiovascular risk. Third, the study design does not allow for a determination of whether hsCRP levels can predict changes in lupus disease activity or lupus flares. Fourth, the number of patients with active neuropsychiatric involvement was too small to evaluate its relationship to hsCRP levels. Lastly, the study did not include matched control subjects for comparison of hsCRP levels and cardiovascular risk factors.
What do the results mean for you?
The results of this study show that hsCRP is detectable in 77% of lupus patients with active disease and that hsCRP levels correlate significantly with lupus disease activity, especially that involving the musculoskeletal system, hematological system, and serositis. Elevated hsCRP levels were significantly associated with cardiovascular disease risk factors in individuals with lupus.
High-sensitivity C-reactive protein, disease activity, and cardiovascular risk factors in systemic lupus erythematosus.
Mok C, Birmingham D, Ho L, Hebert L, and Rovin B. (2012).
Arthritis Care & Research.
2012 September 4.