Markers of Disease Activity
Today, both anti-DNA and complement are still used as markers of disease activity in lupus, particularly for renal disease. Anti-DNA is the only type of anti-nuclear antibody routinely used for this purpose.8
However, not all patients with lupus nephritis show anti-DNA antibodies and/or low complement levels, and not all people with anti-DNA antibodies and low complement levels have renal disease with active flares. These antibodies can be found in some patients who are not experiencing active clinical flares and in some who have never had renal disease. Corresponding to Dr. Schur’s original findings, DNA/anti-DNA complexes clearly aren’t the only elements in play for all patients.
Some investigators have suggested the discrepancy between clinical and serological findings might mean that not all anti-DNA antibodies are truly pathogenic, at least as detected by current assays.7 Notes Dr. Schur, “We now know that low blood complement basically correlates best with type III and type IV nephritis. Not all patients with lupus nephritis have type III or type IV, though it’s well over 50%. And low complement levels don’t correlate that well with other clinical manifestations.”
Dr. Pisetsky explains that, practically speaking, it’s unlikely an increase in anti-DNA antibodies can be used routinely to predict a flare, but it might be immunologically apparent if tested. He describes a lupus patient he recently saw who had a rising creatinine level, for whom he ordered anti-DNA and complement testing. “Now the question is when did that anti-DNA go up? Was it last week? Two weeks ago? Two months ago? We don’t know. So while I’m going to follow the levels, there is always uncertainty,” he says. However, anti-DNA is not a helpful marker in all cases of lupus nephritis.
Many studies have examined which tests might best be used to measure active lupus and lupus nephritis. As Dr. Schur notes, “People are looking for better assays or better ways to look at the assays.” But complement and anti-DNA remain on that list. Says Dr. Pisetsky, “We still haven’t really come up with a better test.”
Dr. Schur points out the correlation of anti-DNA with active lupus nephritis somewhat depends on how exactly you measure it. He adds, “A lot of clinicians just assume an anti-DNA is an anti-DNA, but it has been demonstrated since the 1970s and 80s that a lot depends on which assay you use.”
Similarly, Dr. Schur notes that the currently performed tests for C3 and C4 do not correlate as well with lupus nephritis as the CH50 test he used in The New England Journal of Medicine paper. Research into complement activation products—fragments formed upon complement activation—is also ongoing. Some work suggests such products as C4d also may also be used to diagnose active lupus nephritis and potentially help predict disease flares.9
As Dr. Pisetsky notes, “The fact that we are still asking the question says that the original findings reported by Schur still have a lot of resonance in the field, because we are still trying to find a better way of looking at complement and anti-DNA.”
He summarizes what makes the paper stand out, over 50 years later. “The elements are all there: The fact that there are immune complexes; that these antibodies go up and then go down; that DNA comes into the blood at least sometimes in active disease; that immune complexes form; that the presence of complexes is associated with inflammation. I just think it is one of those papers that unites a lot of elements and points in a lot of interesting directions.”
Dr. Pisetsky adds, “Papers like this have a long lifetime. I always say, ‘The paper doesn’t give you the answers; the paper gives you the questions.’ Why do the DNA antibodies go up and down? What accounts for the variable appearance of DNA in the blood? What are the mechanisms by which the inflammation gets under control? Why are these complexes so pathogenic? All those questions are right there.”
