Proteins on blood cells more accurately predict lupus disease activity

Lupus Foundation of America

Resource Content

What is the topic?

There are a number of ways that a doctor can monitor people to try to predict lupus flares, and they all have advantages and disadvantages. The measurement of complement proteins, C4 and C3, in blood samples is widely used in this way. Measurement of two proteins that split off from C4 and C3 (C4d and C3d) and may be increased in the blood during inflammation has also been found useful, although these tests are not widely available at this time.  

What did the researchers hope to learn?

The researchers hoped to learn whether measurement of C3d and C4d would be a more accurate way to test for lupus disease activity when measured while attached to a red blood cell than when they are freely circulating in the blood.  

Who was studied?

157 people with lupus participated in the study at the University of Pittsburgh between August 2000 and January 2005. These patients were mostly Caucasian women with an average age of 41 years who had lupus for an average of eight years.

290 randomly selected people with one of 16 other rheumatic diseases were also included for comparison purposes, as were 256 healthy people. These participants were mostly Caucasian women with an average age of 51 years. 

How was the study conducted?

Most of the healthy people and patients with other rheumatic diseases had only a single study office visit. The lupus patients had three consecutive office visits. At each visit, disease activity was measured using two kinds of tracking systems called SLAM and SELENA-SLEDAI. Patients were divided into three groups based on how active their lupus was: “less active,” “more active,” and “most active.” 

At the time of the study visit, each participant had blood drawn, which the researchers used to study the two inflammatory complement proteins C3d and C4d.

Since people with lupus can have varying levels of C3d and C4d bound to red blood cells (which are not related to disease activity) the researchers factored in this natural variability in their statistical calculations of the study results.

What did the researchers find?

The healthy people and patients with other rheumatic diseases were older and more likely to be Caucasian than the people with lupus. The levels of C3d and C4d bound to red blood cells did not differ by ethnicity.

The people with lupus had higher levels of C3d and C4d bound to red blood cells than the healthy people and those with other rheumatic diseases. This measurement showed a high level of variability in people with lupus. So, levels of these biomarkers vary among lupus patients but also in the same patients over time. In general, the more C3d and C4d were bound to red blood cells, the lower the levels of these proteins could be found freely circulating in the blood. So, measurement of the complement proteins on red blood cells gives the opposite results of their measurement free in blood samples. 

At the first visit, lupus patients having “more active” and “most active” disease activity had higher levels of C3d and C4d bound to red blood cells than did those with “less active” lupus. Levels of C3d and C4d bound to red blood cells were directly related to disease activity levels (as measured by SLAM and modified SELENA-SLEDAI), but this was not the case when considering levels of the traditional test for C3 and C4 circulating freely in the blood. Statistical analyses suggested that levels of C4d bound to red blood cells were more directly related to lupus disease activity than levels of C3d bound to red blood cells. Levels of C4 freely circulating in the blood was not related to lupus disease activity.

What were the limitations of the study?

Most of the patients were Caucasian. In the future, it would also be helpful to know for which patients this test is most accurate over time. If there was a way to identify these patients in advance, the test could become that much more useful.  

What do the results mean for you?

Lupus is a complex disease and it is unlikely that one blood test will serve all of the patients all of the time. However, this study suggests that a more refined way of looking for clues from the complement (inflammatory) proteins might be an improvement over tests that are commonly used today.

Erythrocyte C3d and C4d for monitoring disease activity in systemic lupus erythematosus.
Kao AH, Navratil JS, Ruffing MJ, Liu CC, Hawkins D, McKinnon KM, Danchenko N, Ahearn JM, and Manzi S. (2010). 
Arthritis & Rheumatism 62: 837-844.