Serum amyloid a protein level, and its significance in systemic lupus erythematosus patients
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AbstractObjective: To investigate The level of serum amyloid A protein (SAA) in systemic lupus erythematosus (SLE) patients and its importance in disease activity.
Materials and Methods: Forty- two female patients who satisfied four or more of the revised ACR criteria for SLE were included in this study. Fifteen healthy female subjects matched for age were included as controls. Disease activity was assessed by the systemic lupus activity measurement (SLAM) index. Serum amyloid A protein was measured by the particle enhanced nephelometry technique.
Results: Serum amyloid A protein (SAA) levels in SLE patients (95.27±100.62 mg/l) were higher than in the controls (4.08+1.14 mg/l) and the difference was statistically significant. Correlation between the SAA level and some of the disease parameters revealed a statistically significant positive correlation with the SLAM index score, prednisone dose and C-reactive protein. No significant correlation was found with age, disease duration, C3, C4, total leucocytic count, ESR or hemoglobin. Serum AA was significantly higher among patients with lupus nephritis
Conclusion: Raised levels of SAA may indicate disease activity as well as lupus nephritis in SLE patients but can’t be used for monitoring of responses in patients receiving systemic corticosteroid therapy.
Serum amyloid A (SAA), is a putative precursor molecule of amyloid-A (AA) protein, formed by proteolytic cleavage by macrophage or polymorph proteinases.
It acts as an acute phase reactant, its concentration increases by up to 1000-fold during inflammation, largely owing to cytokine-driven transcriptional upregulation.
SAA can be used as a marker of inflammation in some autoimmune disorders such as rheumatoid arthritis, and vasculitis  It has a number of immunomodulatory roles. It can induce chemotaxis and adhesion molecule expression and has cytokine-like properties. SAA was found to promote the upregulation of metalloproteinases  and to induce collagenase production, providing a means of remodeling the extracellular matrix in areas of inflammation .
SAA transiently binds high density lipoproteins-3- (HDL3)to macrophages during an inflammatory response. In this way, it can mediate the delivery of lipids to sites of injury for use in tissue regeneration. However, in chronic inflammatory conditions, persistently high levels of SAA may compromise normal cholesterol transport and contribute to the development of atherosclerosis . Binding sites on the SAA protein for calcium, laminin, and heparin /heparan-sulfate are described as well indicating its ability to affect cell adhesion, migration, proliferation and aggregation.
SAA is therefore involved in various physiological and pathological processes, including inflammation, atherosclerosis and thrombosis . The role of elevated levels of SAA over time in predisposision to secondary amyloidosis is debatable.
Acute phase serum amyloid A has been reported to be more sensitive than C-reactive protein (CRP) as a marker of disease activity in rheumatoid arthritis . In this study the profile of SAA in systemic lupus erythematosus patients was studied in relation to clinical manifestations and disease activity.
Forty two patients with systemic lupus erythematosus (SLE), attending the
Rheumatology and Rehabilitation, internal medicine and dermatology outpatient
clinics of Cairo University Hospitals were included in this work. Their ages
ranged from 20 to 47 years and the disease duration from 0.25 to 15 years. All
patients satisfied 4 or more of the revised American College of Rheumatology (ACR)
criteria for classification of SLE [11, 12].
Fifteen healthy female subjects with matched ages served as controls.
B. Clinical assessment:
Full history taking, clinical examination and laboratory investigations were
tabulated in accordance to the systemic lupus activity measurement (SLAM) index
. This index covers the symptoms that occurred over the
previous month and includes 24 clinical and 8 laboratory variables. In addition
serum ANA, anti-n-DNA, serum complement “C3 and C4” and C-reactive protein were
C. Assessment of serum amyloid A:
- Collection of samples: 5 ml venous samples were withdrawn from patients and
controls and stored frozen at –200C.
- Determination of SAA was done by the particle-enhanced immunonephelometry
method , on the Behring Nephelometer (BN II), Dade Behring
Inc., N.Y., U.S.A.
Statistical Methods: Data were processed on a personal computer utilizing the SPSS® 13.0 for Windows® statistical package. Student’s t-test was used when
appropriate. Two-tailed analysis with P value less than 0.05 was considered
significant. Range, mean, and standard deviations are given. Correlation
analysis was performed using Pearson’s correlation.
The general characteristics and clinical features of the studied group are
shown in table (1).
The mean serum amyloid A in systemic lupus erythematosus patients was significantly higher than the control group. This suggests that SAA might be related to the disease process in SLE. Other workers have reported that SAA levels are greatly elevated in rheumatoid arthritis [8, 17]and correlated significantly with disease activity. In SLE some authors reported high SAA levels in patients with active disease but lower than those seen in RA patients . Others found that SAA levels in patients with SLE were only modestly raised, even in those with severe active disease, unless significant intercurrent microbial infection was also present . However SLE patients with obvious infections were not included in the current study.
When SAA levels where studied in relation to disease activity parameters in
the studied group, SAA showed a significant positive correlation with the SLAM
index score, C-reactive protein and insignificantly correlated to the ESR. This
significant correlation indicates that disease activity in SLE is associated
with raised SAA levels. This finding could suggest that SAA may be useful as a
disease activity marker in patients with SLE.
The failure to detect a significant correlation between the SAA level and the
ESR may be attributed to the fact that ESR is only an indirect measure of
disease activity and reflects mainly fibrinogen levels. Furthermore, changes in
the ESR occur slowly and are influenced by factors such as anemia, the size and
shape of red blood cells, lipid levels, and hypergammaglobulinemia .
In this study no correlation could be detected between SAA levels and the
presence of arthritis. When compared to ESR or C-reactive protein SAA is
considered the best marker available for the assessment of inflammatory joint
disease in rheumatoid arthritis and ankylosing spondylitis [4,
8, 25]. However according to our findings, this seems not
to be the case for joint inflammation associated with SLE.
High levels of SAA were found to correspond with the incidence of reactive systemic amyloidosis in SLE and other inflammatory diseases . Autoantibodies to amyloid A protein were demonstrated in one third of SLE cases but their presence was not significantly associated with the development of secondary amyloidosis . Recent studies showed that high concentration of SAA is not sufficient for the development of amyloidosis and that genetic susceptibility through polymorphism of the SAA gene is an important back ground of amyloidogenesis [30, 31]. Those susceptible patients with high risk alleles (SAA 1.5) may be liable to develop reactive amyloidosis .
The present study implied a positively significant correlation of SAA levels in SLE patients under treatment, with the dose of prednisone they were receiving. This might be due to the fact that more severe cases required higher doses of prednisone. On the other hand corticosteroid hormones including dexamethasone, corticosterone, hydrocortisone, and aldosterone may be involved in the upregulation of SAA mRNA expression and thereby increase SAA production . They may affect the synthesis of this protein through altering the production of several cytokines as IL-1, IL-6 [34, 35]. Therefore if elevation of SAA levels is implicated in in the development of amyloidosis, the propriety of using corticosteroid treatment to the patients at risk should be considered .
In this study patients who hasn’t received treatment had significantly higher
levels of SAA compared to normal controls. These levels were signifcantly lower
when compared to those who received treatment regardless their response to
treatment. This would support the explanation of the positive correlation
between the SAA level and prednisone dose received, is secondary to the
stimulatory effect of systemic steroid therapy on SAA. This finiding may
partially negate its value in monitoring the response to treatment.
As regards to the clinical manifestations, in our study the mean SAA level was significantly higher among patients with lupus nephritis. A significant relationship between elevated levels of SAA and renal disease was reported  to be due to the presence of inflammation, as evidenced by increased levels of specific cytokines .
We could therefore conclude that elevated SAA level is a marker that reflects disease activity in SLE patients especially in cases with nephritis. Since SAA level correlates positively with corticosteroid doses received, it cannot be used for monitoring the response of treatment in patients receiving this medication.
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