This is a collection of amazing explanations from Al, my new Weggie friend who has obviously seen the world inside our bodies through some fantastical 'Inner Space' ship. His way of explaining this very complicated stuff is outta this world, and there is talk about maybe changing the forum where this was originally posted (which would mean loosing all of this stuff) so I'm putting it on here for safe keeping and easy reference. Hope you don't mind Al.
Q: Can anyone explain more about the ANCA tests? These seem to be important markers for indicating initial diagnosis and WG flaring, remission, etc. This area is foggy to me. Any help is appreciated!
A: ANCA tests are accurate; it's the interpretation that is dicey. The test determines the titer of certain kinds of ANCA (most commonly anti-PR-3 for GPA, aka Wegener's, and anti-MPO for MPA) But ANCA are only "associated" with the disease, and need corroborating evidence--usually histological, which means that actual samples (like from a biopsy) have been looked at under a microscope. Here, ANCA show as C-ANCA (associated with PR-3) and P-ANCA (associted with MPO). Now, ANCA are Immunoglobulin G (IgG) antibodies, produced by B cells. There are four subclasses of IgG antibodies, and ANCA can fall into all four categories. But the ANCA test does not distinguish among the four kinds. If it did, the test might be a better indicator of disease activity. Current thinking is that ANCA are, in fact, directly involved in the disease process--but not, perhaps, all ANCA. For kidney involvement, IgG subtype 3 seems to be the nastiest, in that patients may be in remission with a relatively high ANCA titer, but not when there is a substantial population of subtype 3 ANCA. The other evidence is physiological: granulomas and such seen in important tissue samples. For GPA sufferers, those of the upper airway and ears (and often other parts) are legendary (and painfully obvious).
In my case, my ANCA are of the anti-MPO type (P-ANCA), and I have very little, if any, upper airway involvement. Heaviest hit are the kidneys, and, to a lesser amount, the lungs. Unlike many people on the forum, I don't have unbearable joint pain. Some, of course, but fortunately, I can deal with it without drugs--which is good, because I am disallowed NSAIDS (aspirin and such), and I don't really trust Tylenol. Heavy kidney involvement, by the way, requires a different maintenance protocol than many here are on. MTX is not kidney friendly, so generally AZA (Imuran) and MMF (CellCept) are prescribed.
You didn't say what type or types of ANCA showed up on your blood work, or what the pathologist said about any biopsy you have had. These would be interesting, though. From a clinical point of view, the strategy is one of triage: first, whack down the inflammation ASAP. This is where the massive amounts of the steroids come into play. (In some cases, like mine, plasma exchange is then employed to sweep out existing antibodies.) Then, keep the immune system from producing new ANCA. This is what CTX and RTX do, though the RTX is specifically targeted at the B cells. CTX more globally bashes the immune system.
The relationship of infection, which, of course, is what the immune system is largely concerned with, and our disease is rather complicated. For purposes of determining likelihood of a relapse, you need both a lot of ANCA around, and a lot of cytokines, which are released in massive numbers during infections. Of course, one of the purposes of immunosupressive therapy is to tamp down cytokine production--but that leads to the higher rsik of infection. So it is a double-edged sword, perhaps the most vexing part of designing a maintenance strategy.
I hope this helps!
Al
Q: what does ANCA stand for? And the P and C designations added...
A: ANCA is an acronym for Anti-Neutrophil Cytoplasmic Antibodies (or Autoantibodies).
Neutrophils are the most common of the leukocytes (while blood cells). They are an important component of the immune system--sort of like naval aircraft carriers, in that they ferry heavy armaments, called granules, into battle zones. )The other two types of granulocytes are eosinophils and basophophils. They are important for dealing with other presumed invaders, and are heavily involved with hypersensitivity reactions.) Actually, this is only part of what neutrophils do. They also directly ingest certain invaders, for instance. And, through a mechanism kind of like a spider web, they trap other invaders. Anyway, During certain infections, or presumed infections, Neutrophils "degranulate". That is, the granules, PR-3 and MPO enzymes, for example, come to the cell's surface, so that they are ready for battle (PR-3 and MPO are deadly to invaders; unfortunately for Weggies, they are also deadly to innocent bystanders). In the language of medical literature, the neutrophils are now "primed"--and, unfortunately, a target for ANCA, which are kind of like mindless drones that assume the granules are targets. This kills the neutrophil. When this happens in close vascular quarters, like in the small blood vessels of the lungs and kidneys, it is like an aircraft carrier blowing up in a harbor's entrance: it blocks everything up and destroys a lot of the surrounding territory. Granulomas consist of a lot of dead cells of varying kinds, but they are mostly collateral damage.
The "P" in P-ANCA stands for Perinuclear; the "C" for Cytoplasmic. These terms refer to the staining pattern that is seen under under a microscope. Anti-MPO ANCA generally show the perinuclear pattern; anti-PR-3 ANCA generally show the cytoplasmic pattern.
Most sufferers of ANCA disease test positive for only one of these types, though some test positive for both. There are, additionally, sometimes ANCA that are called "atypical" and show neither staining pattern. One more complication of interest to us: Some recent research suggests the importance of yet another ANCA type that is not now tested for. This is the anti-LAMP2 antibody. LAMP, or Human LMP, is a naturally occurring protein that, significantly, highly resembles parts of certain bacteria, including some strains of E. Coli. The theory is that an immune system trained on such bacteria will develop antibodies (ANCA) that are now ready to attack anything that looks like, say, E. Coli, including normal cells. (This process is called "molecular mimicry".) Though this research remains to be confirmed, the presence of anti-LAMP2 ANCA is acknowledged by everyone; they can co-exist with anti-MPO and anti-PR-3 ANCA. For me, this theory, or something similar, has a ring of truth, as I suspect my original trigger was a bout of serious intestinal infection. No culture was ever made of my bug, but, from the symptoms, I surmise that is was E. Coli or Salmonella or similar.
Al
Wegener's Granulomatosis. A rare auto-immune disease affecting 1 in 30,000 to 40,000 lucky winners. I'm one of those winners. Diagnosed in May 2010, life has changed dramatically in some cases for the worse and in some for the better. This is where I ramble on about my observations with this new friend called Wegener's - which makes me a Weggie (pronounced 'weg-ee')
