Dr. Mok has received consultant fees, speaking fees, and/or honoraria (less than $10,000) from Pfizer.
Systemic Lupus Erythematosus
High-sensitivity C-reactive protein, disease activity, and cardiovascular risk factors in systemic lupus erythematosus†
Version of Record online: 26 FEB 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis Care & Research
Volume 65, Issue 3, pages 441–447, March 2013
How to Cite
Mok, C. C., Birmingham, D. J., Ho, L. Y., Hebert, L. A. and Rovin, B. H. (2013), High-sensitivity C-reactive protein, disease activity, and cardiovascular risk factors in systemic lupus erythematosus. Arthritis Care Res, 65: 441–447. doi: 10.1002/acr.21841
The content presented herein is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the NIH.
- Issue online: 21 FEB 2013
- Version of Record online: 26 FEB 2013
- Accepted manuscript online: 4 SEP 2012 09:24AM EST
- Manuscript Accepted: 24 AUG 2012
- Manuscript Received: 20 APR 2012
- National Center for Advancing Translational Sciences. Grant Numbers: 8KL2TR000112-05, 8UL1TR000090-05, 8TL1TR000091-05
To study the level of high-sensitivity C-reactive protein (hsCRP) and its relationship with disease activity, damage, and cardiovascular risk factors in patients with systemic lupus erythematosus (SLE).
Consecutive patients who fulfilled ≥4 American College of Rheumatology criteria for SLE who did not have a concurrent infection were recruited. Blood was assayed for hsCRP level, and disease activity, organ damage of SLE, and cardiovascular risk factors were assessed. Linear regression analyses were performed for the relationship between hsCRP levels, SLE activity, damage, and cardiovascular risk factors.
In total, 289 patients were studied (94% women, mean ± SD age 39.0 ± 13.1 years, and mean ± SD SLE duration 7.8 ± 6.7 years). The mean ± SD Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was 4.9 ± 5.6 and clinically active SLE was present in 122 patients (42%). The mean ± SD hsCRP level was 4.87 ± 12.7 mg/liter, and 28 patients with active SLE (23%) had an undetectable hsCRP level (<0.3 mg/liter). The linear regression analyses revealed a significant correlation between hsCRP level and musculoskeletal disease (β = 0.21), hematologic disease (β = 0.19), active serositis (β = 0.46), and clinical SLEDAI score (β = 0.24) after adjusting for age, sex, body mass index, serum creatinine, and the use of various medications (P < 0.005 for all). hsCRP levels correlated significantly with anti–double-stranded DNA titer (β = 0.33, P < 0.001) but did not correlate with complement C3 (β = −0.07, P = 0.26). An hsCRP level >3 mg/liter was significantly associated with male sex, long-term smoking, diabetes mellitus, a higher atherogenic index, and a history of arterial thrombosis. hsCRP levels correlated significantly with pulmonary and endocrine damage scores.
hsCRP was detectable in 77% of SLE patients with clinically active disease and correlated with SLEDAI scores, particularly in serositis and in the musculoskeletal and hematologic systems. Elevated hsCRP levels in SLE were associated with certain cardiovascular risk factors and a history of arterial thromboembolism.
C-reactive protein (CRP) is an acute-phase reactant synthesized mainly by hepatocytes in response to cytokines such as interleukin-6 (IL-6), IL-1β, and tumor necrosis factor α (TNFα). Elevation of CRP level is an essential component of the acute-phase response to a variety of cellular abnormalities such as infection, inflammation, tissue trauma, and malignancies (1). The genes coding for CRP have been mapped to the long arm of chromosome 1 (2). Basal CRP levels are independently influenced by 2 polymorphisms at the CRP locus, namely the CRP 2 and CRP 4 alleles (3). CRP binds to polysaccharides of microorganisms and plays a role in the activation of the classical complement pathway, as well as in the clearance of apoptotic cells (4).
In chronic rheumatic diseases such as rheumatoid arthritis and systemic vasculitis, the CRP level correlates with disease activity. CRP is in fact one of the components of many disease activity indices used for disease activity assessment of inflammatory arthritis (5). However, in patients with systemic lupus erythematosus (SLE), the CRP response to disease activity is intriguing. It is well recognized that CRP levels are either normal or only modestly elevated in patients with active SLE (6, 7). The explanation for this phenomenon is still unclear, although there are postulations, such as the presence of anti-CRP that enhances the clearance of serum CRP (8), genetic polymorphisms that lead to altered CRP production (9), and the altered hepatic response of CRP production to IL-6 and TNFα (10). However, these hypotheses cannot explain the appropriate CRP response of SLE patients to other situations such as the presence of intercurrent infections.
A conventional CRP assay typically measures CRP at levels above 3 mg/liter. A novel high-sensitivity CRP (hsCRP) assay can now detect CRP at a level as low as 0.3 mg/liter. Several recent studies of hsCRP in SLE patients have yielded conflicting results (11–13). Barnes et al (11) reported that hsCRP levels were significantly higher in SLE patients than controls; however, hsCRP levels did not correlate with SLE disease activity scores. Two other studies demonstrated that hsCRP levels correlated significantly with SLE activity (12, 13). Adding to this complexity, a longitudinal study of risk factors and markers of lupus flares did not find an independent relationship between hsCRP levels and the onset of lupus nephritis flares (14). Although the hsCRP level has been demonstrated to be an independent risk factor of cardiovascular disease in the general population (15), there is a paucity of data regarding hsCRP level and cardiovascular risk in SLE. Three studies have reported an association of hsCRP with certain factors such as age, blood pressure, body weight, smoking, menopause, and apolipoprotein A-I in SLE patients (11, 12, 16), but the results were not consistent. Moreover, in one of these studies (12), hsCRP levels were found to be higher in African Americans than other racial groups, suggesting that racial differences may confound the relationship between hsCRP and cardiovascular risk. Racial differences in other cardiovascular risk factors in SLE would further complicate this relationship, such as the increased frequency of arterial thrombosis in Chinese and African American SLE patients compared to white SLE patients (17).
Given the controversy in the relationship between hsCRP, disease activity, and cardiovascular risk in patients with SLE, and the relative lack of data regarding Chinese patients, we conducted this study in an attempt to bridge the knowledge gap regarding the role of hsCRP in SLE.
Significance & Innovations
Using a high-sensitivity assay, C-reactive protein (CRP) was detectable in 77% of systemic lupus erythematosus (SLE) patients with clinically active SLE.
High-sensitivity CRP (hsCRP) levels correlate significantly with Systemic Lupus Erythematosus Disease Activity Index scores, particularly those related to active serositis and musculoskeletal and hematologic disease, as well as pulmonary and endocrine damage.
Elevated hsCRP levels (>3 mg/liter) are associated with male sex, long-term smoking, diabetes mellitus, higher atherogenic index, and a history of arterial thrombosis.
hsCRP is a potentially useful marker for disease activity and cardiovascular risk in patients with SLE.
PATIENTS AND METHODS
Consecutive adult patients fulfilling ≥4 of the American College of Rheumatology criteria for the classification of SLE (18) who attended our outpatient rheumatology clinics or were admitted to the medical wards within a 3-month period from April to June 2008 were recruited for this study. The exclusion criteria were 1) patients having evidence of active infection at the time of venipuncture, as confirmed by culture, viral antigen test, or serologic test, or judged to have an infection by the attending physicians with or without the use of antibiotics or antiviral agents for treatment, and 2) a serum creatinine level >200 μmoles/liter. Informed consent was obtained from the participants and the study was approved by the research and ethics committee of our hospital.
Blood was taken from the participants at 9 AM for the assay of hsCRP and other markers of disease activity that included anti–double-stranded DNA (anti-dsDNA) titer and complement C3 level. Clinical activity and organ damage of SLE were assessed using standard tools; cardiovascular risk factors were also assessed in the same setting. The cardiovascular risk factors included body mass index (BMI), lipid profile, smoking status, and the presence of diabetes mellitus and hypertension. Diabetes mellitus was defined as a fasting blood glucose level ≥7.0 mmoles/liter or a level that required drug therapy. Patients were regarded as having hypertension when their blood pressure was ≥140/90 mm Hg on 2 occasions or antihypertensive therapy was initiated. The antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies) were obtained and data on the regular medications participants were taking at the time of venipuncture were also collected. Blood was taken before any modification of drug doses or addition of new drugs.
Regression analyses were performed between hsCRP, anti-dsDNA titers, complement levels, disease activity, and damage scores of SLE. Cardiovascular risk factors and history of arterial thrombosis were also compared between patients with different hsCRP levels.
Assay of hsCRP, anti-dsDNA, and complement levels.
hsCRP levels were measured in serum samples using a solid-phase chemiluminescence immunometric assay with the IMMULITE 1000 system (Siemens Healthcare Diagnostics). Analytical sensitivity for this assay is 0.01 mg/liter, with a reportable range of 0.3–100 mg/liter. The intraassay coefficient of variation is 3.1% and interassay coefficient of variation is 7.3%. For the purpose of statistical analyses, a value of 0.15 mg/liter was taken for samples with an hsCRP level <0.3 mg/liter. Anti-dsDNA was measured by a commercially available enzyme-linked immunosorbent assay kit (Euro Diagnostica), and complement levels were measured by immunonephelometry (Siemens). An anti-dsDNA titer ≥50 IU/ml was regarded as a positive test.
Assessment of SLE activity and damage.
The disease activity of SLE was assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), a validated instrument employed in the SELENA trials (19). The SELENA–SLEDAI scores were obtained from all patients at the time of the venipuncture. For the correlation studies, the clinical SLEDAI score referred to the SLEDAI score after the deduction of points due to decreased complements (C3 <0.75 gm/liter and/or C4 <0.14 gm/liter) or elevated anti-dsDNA titers (≥50 IU/ml) from the total SLEDAI score. The physician's global assessment of disease activity (PGA; score range 0–3) was also performed by the attending physicians to grade their impression of the disease activity of the patients (20).
Organ damage of SLE was measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) (21), a validated instrument consisting of 41 items that measure irreversible organ damage unrelated to active inflammation in 12 organ systems. Each item should be present for at least 6 consecutive months in order to be scored.
Unless otherwise stated, values in this study were expressed as the mean ± SD. Comparison of hsCRP levels between patients with and without disease activity in different systems was performed by the nonparametric Mann-Whitney U test. Linear regression models were established to study the correlation between the hsCRP level and disease activity score in different systems, with adjustment for age, sex, BMI, serum creatinine, and the use of concomitant medications such as corticosteroids, hydroxychloroquine, mycophenolate mofetil, azathioprine, calcineurin inhibitors, and statins. A comparison of cardiovascular risk factors (both continuous and categorical variables) between patients with hsCRP levels >3.0 and ≤3.0 mg/liter was performed by linear regression, with adjustment for serum creatinine level and SLEDAI scores. The correlation between hsCRP and the SDI score was also studied by linear regression, with adjustment for age, sex, BMI, serum creatinine, and concomitant SLEDAI scores.
The sensitivity and specificity of positive anti-dsDNA (≥50 IU/ml) and hsCRP level (>3 mg/liter) for the detection of concurrent lupus activity were calculated using 2 × 2 contingency tables. A positive outcome referred to the presence of clinical SLE activity, while a positive test referred to a positive anti-dsDNA or hsCRP (>3mg/liter). Sensitivity was calculated by the ratio of true-positive to true-positive plus false-negative. Specificity was equal to true-negative divided by the sum of true-negative and false-positive. Statistical significance was defined as a 2-tailed P value less than 0.05. All statistical analyses were performed using SPSS, version 11.5 for Windows Vista.
Characteristics of the participants.
In total, 332 adult patients with SLE (74% of all patients in our cohort) were invited for this study. Twenty-seven patients refused to participate and 16 patients were excluded (evidence of active infection in 14 patients and renal impairment in 2). Two hundred eighty-nine patients with SLE (including 28 hospitalized patients) were studied (94% women). The mean ± SD age of these patients was 39.0 ± 13.1 years and the mean ± SD duration of SLE at the time of recruitment was 7.8 ± 6.7 years. Table 1 shows the cumulative clinical manifestations and autoantibody profile of the participants. One hundred twenty-five patients (43%) had organ damage, as defined by an SDI score of ≥1 point. The mean ± SD SDI score of the patients was 0.81 ± 1.18 (median 0 [interquartile range (IQR) 1]). The medications the participants were receiving at the time of blood taking were prednisolone (73%), hydroxychloroquine (51%), azathioprine (37%), mycophenolate mofetil (8%), cyclophosphamide (3%), calcineurin inhibitors (8%), statins (9%), and angiotensin-converting enzyme (ACE) inhibitors (29%).
|Clinical manifestations†||No. (%)|
|Facial rash||140 (48)|
|Raynaud's phenomenon||51 (18)|
|Discoid lupus||25 (9)|
|Mucosal ulceration||45 (16)|
|Hemolytic anemia||53 (18)|
|Leukopenia (<4 × 109/liter)||115 (40)|
|Thrombocytopenia (<100 × 109/liter)||74 (26)|
|Lymphopenia (<1.5 × 109/liter)||206 (71)|
|Acute confusional state||3 (1)|
|Neuropathy (peripheral or cranial)||5 (2)|
|Optic neuritis||2 (1)|
Disease activity and hsCRP level.
Of the patients studied, 122 (42%) had clinical SLE activity, with and without elevated anti-dsDNA or decreased complement levels. The mean ± SD total SLEDAI score of the patients was 4.88 ± 5.55 (median 4 [IQR 4]), and the mean ± SD PGA score was 0.74 ± 0.75 (median 0.5 [IQR 1.2]). The clinical disease activity of the patients in various systems within the domains of the SLEDAI is shown in Table 2. Renal activity was most frequent, followed by dermatologic, hematologic, and musculoskeletal activity. Active SLE serology (either elevated anti-dsDNA or decreased complements) was present in 72% of the participants.
|Clinical disease activity||No. (%)|
|Proteinuria >0.5 gm/day or new increase of 0.5 gm/day||63 (21.8)|
|Hematuria (>5 RBCs/hpf) ± active casts||26 (9.0)|
|Pyuria (>5 WBCs/hpf) ± active casts||7 (2.4)|
|WBC count <3.0 × 109/liter||38 (13.1)|
|Platelet count <100 × 109/liter||6 (2.1)|
|Arthritis of >2 joints||25 (8.7)|
|Lupus skin rash (including discoid rash)||34 (11.8)|
|Mucosal ulceration (oral/nasal)||22 (3.8)|
|Cutaneous vasculitis||8 (2.8)|
|Fever >38°C||9 (3.1)|
The mean ± SD hsCRP level in the participants was 4.87 ± 12.7 mg/liter (median 0.99 mg/liter [IQR 3.17]). Of the 122 patients with clinically active SLE, 28 (23%) did not have detectable hsCRP levels (<0.3 mg/liter). In contrast, of 64 patients who did not have clinical or serologic activity (SLEDAI score 0), 51 (80%) had undetectable hsCRP levels.
Table 3 shows the linear regression results of the correlation between hsCRP levels and SLEDAI scores (total, clinical, and individual system) after adjustment for age, sex, BMI, serum creatinine, and concurrent medications being taken, including corticosteroids; hydroxychloroquine; other immunosuppressive agents such as mycophenolate mofetil, azathioprine, and calcineurin inhibitors (cyclosporin A or tacrolimus); statins; and ACE inhibitors. None of the participants were receiving hormone replacement therapy or oral contraceptives at the time of recruitment.
|SLEDAI score||Slope (SE)||β||Adjusted P†|
|Serositis||11.6 (1.33)||0.46||< 0.001|
|Cutaneous vasculitis||0.44 (0.57)||0.05||0.44|
|Total SLEDAI||0.57 (0.14)||0.25||< 0.001|
|Clinical SLEDAI‡||0.64 (0.17)||0.24||< 0.001|
|PGA score||5.40 (1.01)||0.32||< 0.001|
|Anti-dsDNA titer||0.03 (0.005)||0.33||< 0.001|
|Complement C3 level||−3.46 (3.06)||−0.07||0.26|
hsCRP levels were significantly correlated with the SLEDAI scores related to active serositis (β = 0.46, P < 0.001), musculoskeletal disease (β = 0.21, P = 0.001), and hematologic disease (β = 0.19, P = 0.002), with the highest R2 value for serositis (R2 = 0.21 [i.e., 21% of the hsCRP values explained by serositis in the regression model]). A significant association between hsCRP levels and PGA scores was also observed (β = 0.32, P < 0.001). Anti-dsDNA titers correlated significantly with hsCRP levels (β = 0.33, P < 0.001), but not with complement C3 levels (β = −0.07, P = 0.26) after adjustment for the same covariates.
Table 4 shows the hsCRP levels of patients with and without disease activity in various organ systems. The hsCRP levels were the highest in patients with active serositis, followed by musculoskeletal disease (mainly arthritis), hematologic disease (80% leukopenia and 20% thrombocytopenia), dermatologic disease (60% skin rash, 21% mucosal ulceration, and 19% alopecia), cutaneous vasculitis, and renal disease. Significantly higher hsCRP levels were observed in patients who had active musculoskeletal disease, serositis, dermatologic disease, renal disease, and cutaneous vasculitis compared with those who had inactive disease.
|System||Active disease hsCRP level, mg/liter||Inactive disease hsCRP level, mg/liter||P†|
|Renal||7.53 ± 16.0||4.13 ± 11.6||0.02|
|Hematologic||9.9 ± 19.7||4.03 ± 11.0||0.92|
|Musculoskeletal||13.5 ± 22.0||4.02 ± 11.1||< 0.001|
|Dermatologic||9.64 ± 18.4||3.95 ± 11.1||0.01|
|Neuropsychiatric||4.42 ± 0.65||4.88 ± 12.7||0.16|
|Serositis||34.5 ± 40.9||3.92 ± 9.43||0.005|
|Cutaneous vasculitis||9.51 ± 6.98||4.74 ± 12.8||0.001|
Performance of anti-dsDNA and hsCRP in detecting concurrent SLE activity.
The sensitivity and specificity of positive anti-dsDNA (≥50 IU/ml) and hsCRP (>3 mg/liter) in the detection of clinical SLE activity were calculated. hsCRP at a cutoff of 3 mg/liter was less sensitive (0.35 versus 0.76) but more specific (0.77 versus 0.51) than anti-dsDNA in detecting concurrent clinical SLE activity.
hsCRP levels and cardiovascular risk factors.
Eighty-two (28%) of the 289 SLE patients had hsCRP levels >3 mg/liter. Table 5 shows the prevalence of cardiovascular risk factors in patients with hsCRP levels >3 mg/liter and ≤3 mg/liter. A higher hsCRP level (>3 mg/liter) was significantly associated with male sex, long-term smoking ≥3 years, a history of diabetes mellitus requiring treatment, and arterial thrombosis (P < 0.05 for all, after adjustment for serum creatinine levels and total SLEDAI scores). Moreover, the atherogenic index and the ratio of total to high-density lipoprotein cholesterol were significantly higher in patients with an hsCRP level >3 mg/liter than those with a level ≤3 mg/liter (P < 0.05 for all).
|Risk factors||hsCRP level ≤3.0 mg/liter (n = 207)||hsCRP level >3.0 mg/liter (n = 82)||P†|
|Age, years||39.3 ± 15||38.9 ± 13||0.09|
|Women, no. (%)||201 (97)||72 (88)||0.001|
|Smoking ≥3 years, no. (%)||19 (9)||14 (17)||0.04|
|Diabetes mellitus, no. (%)||3 (1)||5 (6)||0.02|
|Hypertension, no. (%)||39 (19)||20 (24)||0.28|
|LDL cholestrol:HDL cholesterol||1.72 ± 0.69||2.22 ± 2.0||0.06|
|Total cholesterol:HDL cholesterol||3.10 ± 0.87||3.82 ± 2.80||0.03|
|TG:HDL cholesterol||0.90 ± 0.60||1.41 ± 2.3||0.045|
|Atherogenic index‡||−0.123 ± 0.26||−0.004 ± 0.32||0.01|
|BMI, kg/m2||21.8 ± 3.7||22.2 ± 3.8||0.17|
|BMI >27 kg/m2, no. (%)||19 (9)||9 (11)||0.38|
|History of arterial thrombosis, no. (%)||12 (6)||11 (13)||0.01|
hsCRP levels and organ damage in SLE.
hsCRP levels did not significantly correlate with the total SDI score (β = 0.09, P = 0.12) after adjusting for age, sex, serum creatinine, BMI, and SLEDAI score (data not shown). Regarding the SDI score in individual systems, hsCRP levels correlated significantly with pulmonary damage (β = 0.14, P = 0.01) and endocrine damage (β = 0.17, P = 0.005) after adjustment for the same covariates. Pulmonary damage occurred in 13 patients and was contributed by interstitial lung fibrosis in 9 patients (69%), pulmonary hypertension in 3 patients (23%), and pleural fibrosis in 1 patient (8%). All patients with endocrine damage had diabetes mellitus.
The exact biologic role of CRP in inflammation and atherosclerosis is controversial. CRP binds to complements and activates the classical complement pathway, therefore contributing to host defense to microbes by promoting an inflammatory response (1, 4). Conversely, CRP exhibits antiinflammatory actions by contributing to complement regulation through the binding of factor H (22) and by binding to apoptotic materials, which enhances the phagocytosis and clearance of these apoptotic materials (4). CRP is present in atherosclerotic plaques and is capable of binding to lipid fractions, such as low-density lipoprotein (LDL) and very LDL and platelet-activating factor (23, 24). However, whether CRP is an innocent bystander of inflammation or plays a critical role in the inflammatory process that leads to the development of atherosclerosis remains an unresolved issue. Older studies have reported that CRP level by conventional assay was not elevated in active SLE, except for the presence of serositis, polyarthritis, and nephritis (25, 26). With the availability of the high-sensitivity assay, CRP level was more frequently detectable in SLE patients even in the absence of infection (27). In a study conducted in 2005 (11), hsCRP was not found to be correlated with disease activity or damage in 213 patients with SLE. However, more recent studies have reported a significant association between hsCRP levels and disease activity in cohorts of SLE patients (12, 13), particularly with the constitutional, eye, pulmonary, gastrointestinal, neuromotor, and laboratory domains of the activity indices, after adjustment for covariates that might influence hsCRP level. This is consistent with our results that demonstrated that hsCRP was detectable in 77% of SLE patients with active disease and was significantly associated with disease activity in certain systems.
hsCRP has also been associated with damage in SLE. Lee et al (28) reported that hsCRP was associated with total SLE damage scores and scores in the musculoskeletal and pulmonary systems after adjustment for confounding variables. In the LUMINA (LUpus in MInorities, NAture versus nurture) study (13), hsCRP was associated with damage scores of the renal, cardiovascular, pulmonary, musculoskeletal, and endocrine systems on univariate analysis, but did not correlate with the total damage scores in the multivariate model. Our results showed that hsCRP levels correlated with pulmonary and endocrine damage on multivariate analysis. While the association between hsCRP and pulmonary damage (mainly contributed by interstitial fibrosis) is intriguing, the correlation between hsCRP and endocrine damage is attributed by diabetes mellitus, which is a cardiovascular risk factor. Other factors that have been shown by previous studies to influence hsCRP level are age, menopause, renal insufficiency, BMI, and medications such as glucocorticoids, estrogens, statins, and antimalarials (11, 12, 16), which have been adjusted in the regression models of our study.
hsCRP has emerged as an important independent risk factor for cardiovascular events in the general population (15), and it is one of the components of the Reynolds cardiovascular risk score (29). In the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial (30), it was demonstrated that statin treatment in healthy men ages >50 years and women ages >60 years with an LDL cholesterol level <130 mg/dl and an hsCRP level >2 mg/liter reduced the incidence of a major cardiovascular event by 44%. The best cardiovascular outcomes occurred in patients who attained an LDL cholesterol level <70 mg/dl and an hsCRP level <1 mg/liter with statin treatment (31).
Previous studies have reported a significant association between hsCRP and certain cardiovascular risk factors in patients with SLE (11, 12, 16). One study that excluded patients with cardiovascular risk factors revealed an association between higher hsCRP levels and vascular stiffness as assessed by flow-mediated dilation (32). However, in 3 recent studies (33–35), no significant association between hsCRP and carotid atherosclerosis could be demonstrated, despite an older cohort study showing a significant relationship between higher CRP levels at baseline and vascular events (36).
The demonstration of an association between elevated hsCRP levels and certain cardiovascular risk factors in our study suggests that hsCRP may be a surrogate marker for cardiovascular risk in SLE patients. However, caution must be exhibited because the hsCRP level often fluctuates with time because of disease activity and intercurrent infection (16). A spot value of hsCRP, especially during active SLE or infection, may not accurately reflect cardiovascular risk; this might have contributed to the negative relationship between hsCRP and subclinical atherosclerosis in previous studies (33–35). Summating serial hsCRP values over time (area under the curve analysis) obtained during periods of disease quiescence and absence of clinical infection may prove to be more useful in the assessment of cardiovascular risk in SLE patients.
The major limitation of the current study is its cross-sectional design, which prevented us from determining if hsCRP levels could predict changes in SLEDAI scores or lupus flares in different systems. Another limitation is that the number of patients with active neuropsychiatric manifestations was too small to evaluate the correlation between hsCRP and neuropsychiatric disease activity. Moreover, we did not enroll matched control subjects for the comparison of their hsCRP levels and cardiovascular risk factors with those from the SLE patients.
In conclusion, this study demonstrated that CRP, assayed by a high-sensitivity method that was capable of picking up low levels, was detectable in 77% of SLE patients with active disease but no intercurrent infection. hsCRP levels correlated significantly with SLE disease activity scores, especially in the musculoskeletal and hematologic systems and in serositis. hsCRP level at a cutoff of 3 mg/liter was more specific but less sensitive in the detection of concurrent clinical SLE activity than anti-dsDNA positivity. Higher hsCRP levels were associated with pulmonary damage and certain cardiovascular risk factors in SLE patients, such as smoking, male sex, diabetes mellitus, higher atherogenic index, and history of arterial thrombosis. Further studies are necessary to delineate the usefulness of serial hsCRP monitoring in estimating cardiovascular risk in SLE patients so that early preventive strategies can be instituted.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Mok had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Mok, Birmingham, Ho, Hebert, Rovin.
Acquisition of data. Mok, Birmingham, Ho, Hebert, Rovin.
Analysis and interpretation of data. Mok.
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