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Systemic Lupus Erythematosus

Lupus consists of multiple diseases under one heading with multiple manifestations, and to compare a group that has nephritis, exclusively nephritis, to a group that has exclusively CNS disease may not be justified lupus, lupis, systemic lupus erythematosus. Are laboratory serologies useful in the assessment of lupus? Why measuring serological parameters in patients with lupus? Well, what we actually want is to have parameters that directly reflect the pathophysiology of the disease lupus, lupis, systemic lupus erythematosus. Because this would enable us to follow the disease process and its origin and give us the opportunity to see changes at the earliest time in order to come to intervention. Now what do we know? Lupus is a disease of autoantibodies and

Now letís first mainly concentrate on the anti-double stranded DNA antibodies in relation to relapses of lupus. The data are disturbing in the literature. They are not in concordance. But I would like to show you one of our previous studies that we have performed in a cohort of patients with lupus, 72 patients defined based on ACR criteria, and those patients were followed for a median time of 18 Ĺ months. And we took monthly plasma samples from those patients and those sample were assessed for

Now what about these sort of relapses? Well, we dissected relapses in renal and non-renal relapses and as you see, particularly the renal relapses, 12 out of 13 were preceded by a significant rise in the antibodies as measured in the Farr assay. The time period between the occurrence of a significant rise in antibodies and the occurrence of a relapse was 10 weeks for the Farr assay.

Now, what can we say about the specificity of those rises? Letís concentrate on the Farr assay. We observed during that observation period 28 rises in antibodies to double-stranded DNA as measured by Farr assay. And 23 out of those rises were indeed followed by a relapse. So we ended with these five rises in antibodies to double-stranded DNA not followed by a

Now what about the complement components? Well, first let me say, what actually causes the increase in antibodies to double-stranded DNA? Well, unfortunately we donít know. But what we observed was that the rise in antibodies was rather specific for double-stranded DNA because it was, only in a few cases, accompanied by an increase in antibodies to an irrelevant antigen-like, or by an increase in the total level of IgG or IgM. Now how to explain the discrepancies of this study with that of

What we next did when we evaluated those samples in which we observed an increase in levels of anti-DNA, in one assay with the previous samples in order to be sure that we detected a real increase in anti-bodies to double-stranded DNA. We used pretty fine definitions of flares, minor or major flare. Now, what about the complement components? Do they have additional

Now what about other antibodies that seem to more specific, or pathophysiologic, for renal disease. Well, let me give you one example. Antibodies to C1q. Those antibodies were present in 14 out of 17 relapses with renal disease, and in 6 out of 16 with non-renal disease. And incidentally, in patients with inactive disease. Then out of 14 cases that were characterized by an increase in those antibodies prior to the relapse. So there seems to be less sensitive for detecting relapses, even renal relapses.

What about other measurements that reflect immune activation in lupus. Here I show, just as an example, the value of measuring soluble interleukin-2 receptors. In another study we observed that in 16 out of 21 relapses a rise in levels of those receptors preceded the relapse, for a median of 3.5 weeks before the relapse. And 3 out of 5 of those rises were in cases in which there

Yes, I would like to make two comments. The first comment is; I think that when you have a patient in your clinic, the outpatient clinic, who shows signs of lupus activity it probably is not difficult - although you have to differentiate, probably, from other possibilities, other causes - that these patients have active lupus. When I have a patient with severe proteinuria, letís say in

The second point is this; that when you are evaluating all those studies, I have mentioned already the time-frame, how frequently do you measure antibodies. Otherwise it is very important to be sure of the variability of the assays that you use. So in order to come to a conclusion you have to be sure, indeed, that there is not a large inter-assay, or even intra-assay, variability in the tests.

Now, instead of starting with lupus, what Iíd like to start with is what I regard as a great success story. And that is, if one looks at diseases in which we are very clear about the organ that is affected by the disease, if we are clear about the disease course and we have some understanding that the disease course is predictable, that it is chronic and that itís progressive. That we are clear about what clinical variables we are measuring. So in this instance, we are clear that we can see joint swelling, we can measure joint tenderness and moreover, we have some assurance that these things that we are measuring are associated with

Monitoring patients with lupus will only be possible with instruments of measurement. A very interesting proposition. Now letís think about this. Lupus is no RA. Itís a very complex disease, as everybody in this room knows. We are dealing with a disease in which there are a number of organs that are involved in the disease. Thereís a variety of severityís that can be affected and the disease force - unlike something like RA - is quite unpredictable. It is not invariably chronic and progressive, and in fact quite to the contrary. It is relapsing and remitting. Now despite these obstacles, what weíve seen is the development of a number of

So I would end with two brief summary slides. The first is to say that this group of world travelers has certainly made progress. We now have multiple instruments and they are validated and that sounds good. But we are struggling greatly with what the role of these things are. Right? They allow these world travelers to do epidemiologic studies, to write papers and to advance in academia. Industry is wondering what their role is in clinical trials because they invest millions of dollars and then find that these instruments fail them. Matthew Liang suggests that they are terrific for monitoring patients but we are not so sure. Iíd like to end with one final slide, and that is - on behalf of all of you - express my collective thanks to Matt Liang for his enthusiasm, his energy and his leadership in trying to shed light on this nebulous concept of lupus activity and to develop methods which will allow us to do clinical research in this disease. Certainly his efforts have been intellectually stimulating, provocative and certainly providing encouragement that it may be possible to develop some kind of an index in the future that will facilitate clinical research. However, I would suggest to you that there is no reason on earth to believe that these are going to influence our ability to care for our patients with this disease. Thank you very much.

I would like to share with you a patient that I saw when I was a fellow some time ago. I was called up by a fellow who said, "Excuse me, Iíd like to call a consultation. I have a 12-year-old African female who has presented to us with intermittent polyarthritis, seizures, cutaneous ulcerations, abdominal pain, anemia, progressive renal insufficiency and hyperglobulinemia." And I said, "Well, it sounds like this patient may have lupus. What do you want this practice to do?" he said, "Iíd like you to come and see the patient and do a formal consultation." So I said okay and asked for the room number. Then he said, "Before I tell you that, I should also caution you that sheís lost 1,000 pounds in the past year." So my attending and I went out the next day to the Baltimore City Zoo and there I was with the patient. There wasnít much of a history other than what was already told to us to take, but with every good rheumatology consultation we have to do physical examination. My attending had the wisdom of

There are really a lot of important questions to consider when assessing lupus activity, because lupus rarely flares in a vacuum. First of all you have to determine whether or not the clinical flare actually constituted a lupus flare. A patient who is affected with lupus -and all of us who take care of lupus patients knows it is a major problem distinguishing infection when the patient is coming to you with fever or arthritis and pulmonary infiltrates - whether or not this constitutes a lupus flare or instead, an infection or