Historical evolution concept of vasculitis
Vasculitis – An inflammatory process of the blood vessels that appears as palpable purpuric papules. A common form is known as leukocytoclastic vasculitis (process mediated by neutrophils).
The term vasculitis identifies complex medical conditions characterized by blood vessel inflammation and damage. Serious complications result when the vascular lumen is compromised and ischemia results. Vasculitis may be a primary disease or a manifestation of another disease . Typically, vasculitis is systemic. Most vasculitis syndromes affect some tissues or organs more than others. Occasionally the disorder is confined to a single organ, such as the skin.
The diversity of vasculitis syndromes make these conditions a clinical concern for general-medicine physicians as well as specialists. Vasculitis syndromes most likely to be encountered by allergists/immunologists are hypersensitivity vasculitis; ANCA associated vasculitis, including Wegener’s granulomatosis and Churg-Strauss vasculitis (allergic angitis and granulomatosis); and temporal arteritis.
Because the etiology of most vasculitic syndromes is unknown, the development of definitive therapy for these conditions is hampered. Nevertheless, progress continues in refining immunosuppressive treatment and in improving the monitoring of therapy. In addition, diagnostic classification schemes continue to evolve and new testing modalities—particularly antineutrophil cytoplasmic antibody (ANCA) testing—are proving to be clinically useful.
In vasculitis, lesions are purpuric and do not blanch due to blood extravasation from damaged vessels. They are palpable because of inflammation and edema. Vasculitis is commonly associated with systemic conditions such as sepsis and collagen vascular diseases. They can also be due to drug reactions.
Treatment is geared toward the underlying cause or removal or the offending agent. Immunosuppressants are often used to control the inflammatory process.
Microscopically, vasculitis shows inflammatory destruction of a blood vessel wall and can affect different sizes of vessels. The inflammation within the vessel wall can be acute with neutrophils and/or eosinophils, can be granulomatous and also lymphocytic. Usually there is leakage of red cells into the dermis from the damaged vessel (red cell extravasation) and fragmentation of the inflammatory cells involved (leukocytoclasis). Fibrinoid type necrosis of vessel walls can occur. Leukocytoclastic Vasculitis (LCV) is a common type of hypersensitivity vasculitis affecting the small superficial capillaries of the dermis with infiltrates of neutrophils and sometimes eosinophils.
Vasculitis is characterized by inflammation in blood vessel walls Systemic vasculitis, of course, as we are all aware, is a rather complex issue. It is inflammation of vessel walls. It is not inflammation around vessels; it is inflammation of vessel walls. The vasculitis that affect the kidney most often are necrotizing vasculitides that affect parenchymal arteries and also in fact very often vessels other than arteries. You could say vessels smaller than arteries, but it’s really more definitive to say vessels other than arteries. Today we are really going to be concerned with necrotizing vasculitis affecting arteries and other smaller vessels. Large vessel disease. There are large vessel vasculitides that occasionally affect the kidney. These vasculitides by definition affect the aorta and its major branches; and therefore, the major impact on the kidney is through the induction of hypertension.
So renal vascular hypertension because of injury to the aorta at the ostium or involvement of some of the larger arterial radicals leading to the kidney is the major problem in patients with giant cell arteritis and Takayasu’s arteritis. I’m not going to spend any more time discussing those large vessel vasculitides. Medium and small vessel vasculitides Really the more difficult classification and therefore diagnostic problems are with vessels that affect the parenchymal arteries, arterioles, the glomerular capillaries and even other vascular structures, such as the vasa recta within the kidney. So we are going to be concerned with these so-called medium-sized vessel vasculitides, which, by at least the definition at I prefer, indicates that they involve arteries; and small-vessel vasculitides, which means that they involve vessels other than arteries, which of course means vessels smaller than arteries, such as capillaries and venules.
Some of the earliest investigations of patients with vasculitis were prompted by the recognition of arteritis, which in fact could be seen grossly as modular enlargements in the arteries within the parenchyma and even in main visceral arteries such as the renal arteries, hepatic artery. There were many early reports. Certainly Karl Rokitansky described patients with what was in fact arteritis in his discussions of patients with aneurysms. But Kussmaul and Maier in 1866 really published one of the first detailed descriptions of vasculitis in patients. In the one patient that they described most carefully, the involvement was predominantly, at least, within arteries and could be seen grossly; but microscopically, it involved very small vascular radicals as well.
In their patient the presentation was similar to what I’m sure you’ve seen in your own patients. There were the non-specific manifestations of a systemic inflammatory process–fever, anorexia, weakness. There were also indications of vascular involvement in the tissues–myalgia, paresthesia, abdominal pain, cutaneous nodules, and there was oliguria. The gross pathology, as I mentioned and, as was illustrated here in the article by Kussmaul and Maier, was predominantly nodular thickenings along arterial radicals. Histologically this was shown to be inflammation and necrosis.
Renal involvement by polyarteritis nodosa. Note dark thrombosed pseudoaneurysms and pale peripheral infarcts.
Gross changes of medium-sized vessel vasculitis
This is a similar presentation to what was seen and illustrated by Kussmaul and Maier. In this photograph, you can see that these kidneys have large aneurysms filled with clotted blood. These are really not true aneurysms; they are pseudo- aneurysms because actually the inflammatory process has eroded through the vessel wall and into the adjacent parenchyma. So it’s not just a dilation of a vessel–it’s an erosion through a vessel by this necrotizing process. Of course, this process can occlude the arterial arteries that are involved. You can see in the periphery here a number of infarcts, which is a complication of arteritis affecting the larger vessels in the kidney. In fact, there was rupture of one of the aneurysms. This patient actually died from massive hemorrhage into the retroperitoneal and peritoneal cavities. In this patient you can also see the typical nodular inflammatory lesion of polyarteritis nodosa as it’s called today.
Microscopic changes in the pancreas: polyarteritis nodosa
Here we can see an artery within the pancreas. At this point the walls have been eroded through and there is this large pseudo-aneurysm filled with thrombotic material. This process was initially called periarteritis nodosa by Kussmaul and Maier, but soon after the term polyarteritis nodosa became more popular, and nowadays it is really the preferred term because many different vessels are involved and it is really a transmural process, not a perivascular process.
It is found that some vasculitis has granulomatous changes
For over 50 years almost anyone with necrotizing arteritis was called periarteritis nodosa or polyarteritis nodosa. Anybody with necrotizing arteritis was put into that category. But by the 30s, it was becoming clear that there were various patients who had distinctive features in addition to the systemic necrotizing vasculitis that warranted separation into a different category.
Klinger in the early 30s and later his schoolmate, Wegener, described this pattern of granulomatous inflammation associated with the necrotizing vasculitis that we now call Wegener’s granulomatosis. In this process there is systemic small-vessel vasculitis with necrosis. There is arterial involvement frequently with necrosis, and there is granulomatous inflammation, often in the respiratory tract–either the lung or the upper respiratory tract–with a very necrotizing character to it but with scattered multi-nucleated giant cells that have lead to the designation granulomatosis.
Necrotizing and granulomatous arteritis in the lung of a patient with Churg-Strauss syndrome.
Granulomatous inflammation, vasculitis, and eosinophilia
Another variant of this granulomatous inflammation associated with necrotizing vasculitis was described by Churg and Strauss and is now designed Churg-Strauss Syndrome. In these patients there was an associated asthma as well as peripheral eosinophilia, and sometimes their vasculitic and granulomatous process was preceded by a eosinophilic pneumonia or an eosinophilic enteritis. So, again, there was a subset of patients that initially were considered polyarteritis nodosa with asthma. Eventually the terminology evolved such that there was a more specific designation, Churg-Strauss Syndrome, for what appeared to be a clinically pathologic process distinct from usual polyarteritis nodosa.
The beginnings of a classification emerge
So you can see that from the initial single category of necrotizing arteritis, some entities with specific features were being separated. At this point we really had still polyarteritis nodosa, Wegener’s granulomatosis, and Churg-Strauss Syndrome. Zeek and Godman and Churg in the early 50s, and in fact beginning in the late 40s, added some substantial insight into the categories of necrotizing vasculitis. Early classification systems: Zeek (1948, 1952)
Although Zeek’s 1952 article is better known, her 1948 article really describes more carefully her perception of necrotizing vasculitis. And what she concluded was that there were two major forms of necrotizing vasculitis. There was what had been described, she felt, by Kussmaul and Maier that she was at that time calling periarteritis nodosa that had involvement of arteries but had no involvement of the lungs, and it had no involvement of vessels smaller than arteries.
Clinical features of many vasculitis syndromes overlap, and these abnormal conditions are heterogeneous—complicating the diagnosis and classification of affected subjects. Both this heterogeneity and lack of causal identification have hindered the development of a classification system. Available classification schemes are chiefly descriptive, and consensus is occasionally lacking on essential features of each condition.
Figure 1. Classification scheme suggested by the Chapel Hill conference
The Chapel Hill conference provided an organization and classification of vasculitis based principally on the size of the affected vessel (Figure 1). Controversy continues about small-vessel necrotizing arteritis, currently considered microscopic polyangiitis (MPA) in the Chapel Hill classification scheme. Some authorities believe MPA is a component of polyarteritis nodosa. However, MPA should not be confused with small-vessel necrotizing vasculitis, which characterizes Wegener’s granulomatosis and Churg-Strauss syndrome. Neither should MPA be confused with leukocytoclastic vasculitis, typically seen in Henoch-Schonlein purpura or hypersensitivity vasculitis. Usually, small-vessel necrotizing vasculitis affects arterioles, venules, and capillaries. Leukocytoclastic vasculitis affects capillaries and venules generally found in the skin. MPA affects vessels of various sizes, including small arteries, but not muscular arteries as in polyarteritis nodosa. Two series of randomized controlled trials have helped to define the classification of vasculitic syndromes, using ANCA and effective therapeutic regimens.
Primary Vasculitis Syndromes
Giant Cell arteritis
Idiopathic cutaneous vasculitis
Essential mixed cryoglobulinemia
Isolated vasculitis of the central nervous system
Secondary Vasculitis Syndromes
Drug induced vasculitis
Vasculitis associated with other primary diseases
Infection e.g. Hepatitis B associated polyarteritus nodosa
Autoimmune disease (e.g. systemic lupus erythematosus, Sjögren’s Syndrome)
An example of small-vessel necrotizing arteritis.
How the concept of hypersensitivity angiitis evolved
But she also recognized a group of patients who had, in her words, “lesions and small intrinsic venules, arterioles, and small arteries of the viscera, including the lung.”
She also described necrotizing glomerulonephritis as a frequent feature of this lesion, and in fact said that “involvement of arteries that were larger was very rare in these patients.” She, unfortunately in my opinion at least, called this hypersensitivity angiitis because a number of her patients had been treated with sulfa drugs, but of course anyone with inflammatory pulmonary disease at that point in time would have gotten sulfa drugs, I suspect. Also, she had been involved in experimental models of vasculitis induced by positioning silk around the kidneys, which was then felt to be induction of vasculitis by an allergic response to that foreign material. So she called it hypersensitivity angiitis. This term, unfortunately thereafter was used to described many different forms of vasculitis, some with more or less evidence for an allergic pathogenesis.
Zeek’s 1952 classification system for vasculitis
Her 1952 article proposed an actual classification system for vasculitis: What she called periarteritis nodosa; hypersensitivity angiitis, which is a small-vessel necrotizing vasculitis; she was aware of the allergic granulomatosis and angiitis that we now call Churg-Strauss Syndrome; she apparently as not aware of Wegener’s granulomatosis being a type; she also was aware that patients with rheumatic diseases developed forms of vasculitis; and was aware of the large vessel form of vasculitis called temporal arteritis, which is now designated giant cell arteritis because it doesn’t always affect just the temporal arteries.
Godman and Churg’s contributions
Godman and Churg also looked at systemic vasculitides. Of course, Churg had been involved with Strauss earlier in describing Churg-Strauss Syndrome. They came to some conclusions in 1954 which are basically, in my opinion, where we are today. They recognized again that periarteritis nodosa, as it was designated, affected mainly arteries and grossly visible arteries. But they concluded that there was a more common form of vasculitis that they referred to as the “microscopic form of periarteritis nodosa.” They concluded that, in fact, this was the same category of vasculitis that Zeek was calling hypersensitivity angiitis. But they pointed out that there really was not good evidence for allergy in these patients and that isn’t a good terminology. So they preferred the term “microscopic form of periarteritis.” They also, of course, were aware of Wegener’s granulomatosis. In this 1954 article, they clearly described the major triad of Wegener’s granulomatosis with systemic necrotizing angiitis, as they called it; necrotizing glomerulonephritis; and, of course, the granulomatous inflammation. And they also were, of course, aware of Churg-Strauss Syndrome since Churg had just been involved with describing this earlier. They concluded that because of the pathologic similarity, especially of the underlying small-vessel vasculitis, that Wegener’s granulomatosis, Churg-Strauss Syndrome, and microscopic form of periarteritis were related and were distinct from and probably pathogenetically distinct from periarteritis nodosa or what we call polyarteritis nodosa. I would suggest that more recent data that I will review later supports this position that they put forward in 1954. These do appear to be related because they all are associated with ANCA. This process [polyarteritis nodosa], I believe, is distinct and now uncommon as we’ve pulled away from it many more specific forms of vasculitis.
|Small coronary artery with segmental necrosis and inflammation in a patient with Kawasaki disease.|
In the 1960s, the final major category of necrotizing vasculitis was separated from the polyarteritis nodosa group, and this is Kawasaki’s disease. Up until this point, there were other descriptions of this process sometimes referred to as infantile form of polyarteritis nodosa because Kawasaki’s disease occurs most frequently in young children. However, Kawasaki’s disease has another very distinctive component, and this is the mucocutaneous lymph node syndrome. So basically the diagnostic characteristic that separates Kawasaki’s disease from polyarteritis nodosa is this mucocutaneous lymph node syndrome with erythematous and scaly mucosa and skin, especially on the digits, with a lymphadenopathy and with this necrotizing vasculitis that has a predilection for the coronary arteries and can produce aneurysms with thrombosis and myocardial infarction. The necrotizing lesion is similar to that of polyarteritis nodosa, although there are some subtle differences in general — a little less fibrinoid necrosis, a little more cellular character to the initial injury.
It is realized that vasculitis affects vessels other than arteries
Now all of this investigation up until this point has been stimulated by arteritis. So investigators were looking at patients who clearly had involvement of the arteries. But there was a parallel development of categorization of patients with evidence for vasculitis that was taking place based on manifestations of small-vessel vasculitis that was affecting vessels other than arteries.
|Purpura caused by small vessel vasculitis, for example, any form of ANCA-vasculitis, such as microscopic polyangiitis, Wegener’s granulomatosis, or Churg-Strauss syndrome; or immune complex small vessel vasculitis, such as Henoch-Schönlein purpura or cryoglobulinemic vasculitis.|
Purpura and vasculitis: Henoch-Schonlein purpura
The major manifestation that lead to this sequence of parallel but eventually intersecting investigations of patients with vasculitis was purpura. And so in the literature, actually from the Greeks and probably before, there have been clinical descriptions of purpura.
|Dermal leukocytoclastic angiitis, which is the most frequent pathologic lesion causing vasculitic purpura; and can be a component of many types of small vessel vasculitis.|
Some of the earliest elucidations, however, of the syndrome of purpura, which was found eventually to have a substantial renal component, were carried out by Schonlein and later by Henoch. In fact, Henoch gave the more careful description of the full spectrum of small-vessel involvement in what is now sometimes called Henoch-Schonlein purpura. Clearly at the point that they were describing the syndrome, a number of small-vessel vasculitis categories were present in the patients they investigated. Also at the turn of the century, Osler made some major contributions in the evaluation of patients with small-vessel vasculitis and was one of the first to recognize how often renal involvement occurred and how severe it might be in patients with purpura, abdominal pain, and nephritis. Now the reason I think that Osler saw the more severe renal involvement was he was seeing more adults.
Henoch was a pediatrician so most of the patients he saw were children. He saw what today we would call Henoch-Schonlein purpura, with purpura, abdominal pain, and nephritis; whereas Osler was seeing adults, many of whom had microscopic polyangiitis with purpura, abdominal pain, and nephritis. His patients tended to be more severe. In any event, those investigations of patients with purpura pointed out that small-vessel vasculitis can affect the skin, can affect the gut, can affect the kidneys; also peripheral nephropathies were present in some of those patients, and that involvement was recognized.
Massive pulmonary hemorrhage in a patient with Goodpasture’s syndrome.
Involvement of the lung in vasculitis
The next organ system that was recognized to be affected by small-vessel vasculitis in a pattern other than arteritis and granulomatous inflammation was the lung, with hemorrhagic capillaritis causing massive hemorrhage in some patients. Goodpasture is credited with one of the earliest descriptions of a patient with this so-called pulmonary-renal vasculitic syndrome; a patient who, following a flu-like illness developed severe pulmonary hemorrhage and severe glomerulonephritis. Actually at postmortem examination, this patient had small-vessel vasculitis in the spleen and the gut as well. This patient probably had ANCA- associated microscopic polyangiitis. However, Goodpasture’s syndrome, the designation, is now used primarily for patients with evidence for anti-basement membrane disease, as I will return to in a moment.
It is realized that the spectrum of vascular injury can be quite broad
So at this point then from investigations of patients with clinical manifestations of small-vessel vasculitis, it was clear that the spectrum of necrotizing vascular injury was quite broad. Arteries could be involved, venules could be involved, capillaries could be involved in the glomeruli, producing necrotizing glomerular injury, and capillaries in the lungs could be involved. So many tissues could be involved. This was a very complex problem of classification at that point because you had this broad spectrum of vascular and organ system involvement and any number of names that had been applied in varying ways to these. It was quite confusing, not that it’s not still confusing.
Antineutrophil Cytoplasmic Antibodies Clarify the Situation Dr. Jennette
The role that immune complexes play is appreciated
Fortunately some other modalities of diagnostic evaluation came into the picture in the 60s, in particular, and 70s. Immunohistology demonstrated that at least some of these patients with small-vessel vasculitis had immune complexes in the vessel walls, for example, here in the dermis of a patient with leukocytoclastic angiitis histologically and purpura clinically.
A number of immune complex vasculitides were subsequently recognized. Henoch-Schönlein purpura has been redefined and restricted to those patients with IgA-dominant immune complexes as the cause of their small-vessel vasculitis. By that definition, it occurs primarily in children and usually has a good outcome. Cryoglobulinemia vasculitis was recognized by McClusky and his associates initially and, of course, is the result of cryoglobulins, especially Types II and III cryoglobulins localizing in small vessels and inciting inflammation. Lupus can, on occasion, have a systemic vasculitis; rheumatoid arthritis patients occasionally have an immune complex vasculitis; serum sickness vasculitis; infection-associated vasculitis; paraneoplastic vasculitities; some drug-induced vasculitides can show evidence for immune complex deposition.
Allergic vasculitis is hypersensitivity to a drug or foreign substance that leads to inflammation and damage to blood vessels of the skin.
Vasculitis – allergic hypersensitivity; Cutaneous leukocytoclastic vasculitis
Allergic vasculitis is caused by an allergic reaction to a drug or other foreign substance.
- Skin lesions usually located on legs, buttocks, or trunk
- Blisters on the skin
- Urticaria (hives), may last longer than 24 …
Pauci-immune vasculitis is appreciated
For a while it was considered that possibly most, maybe even all, small-vessel vasculitides were caused by immune complex deposition or anti-basement membrane antibodies. And, of course, when you look at the glomerular involvement, which is frequent in patients with small-vessel vasculitis, you certainly do see some patients with granular staining indicative of an immune complex disease and linear staining indicative of anti-basement membrane disease. However, it became apparent to any number of investigators that the involved vessels other than glomeruli as well as the glomeruli in many patients with small-vessel vasculitis, especially patients with Wegener’s granulomatosis and microscopic polyangiitis, did not have staining for immunoglobulin or complement. So this paucity of staining was somewhat of a problem in explaining the pathogenesis.
Prevalence of immune complexes in vasculitis
And in fact, these patients with pauci-immune vasculitis were quite common. For example, in this analysis of patients evaluated in my laboratory, you can see that the pauci-immune category is about equal to the immune complex category and much more frequent that anti-GBM disease if you look at all patients with inflammatory glomerulonephritis. And as you look at more and more severe glomerulonephritis, the frequency of this pauci-immune category goes up even more. So if you look at those patients who have greater than 50 percent of their glomeruli involved with crescents, this pauci-immune category is the most common. And, in fact, if you look at those few patients in whom you see necrotizing vasculitis in addition to glomerulonephritis in the kidney, there is a strong predilection here for the pauci-immune category.
Pauci-immune glomerulonephritis and ANCA positivity
Also in older patients, as has been seen here in Scandinavia by Pedersen and her associates in Stockholm, the frequency of this pauci-immune pattern and in fact this ANCA-associated disease pattern goes up. You can see here in this particular cohort, 90 percent of the patients were ANCA positive. So the pauci-immune category of glomerulonephritis and small-vessel vasculitis almost equates with ANCA vasculitis and glomerulonephritis.
As will be discussed later in detail by Jörgen Wieslander, ANCA specificity, as is well known to this group, in patients with glomerulonephritis vasculitis breaks down primarily into patients with anti-proteinase 3 specific antibodies that react with the cytoplasm and cause the C ANCA staining pattern and anti-myeloproxidase specific autoantibodies that react with antigen that is redistributed to the nucleus artifactually during preparation of the substrate if you use alcohol-fixed neutrophils. So these two ANCA specificities then mark a subset of small-vessel vasculitis that probably have a related pathogenesis.ANCA vasculitis: glomerular and extrarenal involvement patterns
If you look at all patients with ANCA- positive glomerulonephritis, some of them apparently have involvement of no other tissues from all of the evidence that you can collect. But most patients with ANCA-positive glomerulonephritis have evidence for involvement of other viscera. The diagnostic challenge in these patients is to categorize those patients into some specific set if possible. This may be a somewhat academic exercise because, as we will discuss some later, the treatment may be very similar if not identical for all of these categories. So the main step is initially realizing that it is an ANCA-positive necrotizing small-vessel vasculitis and possibly proceeding with treatment at that point and trying to categorize them further. If there is no systemic involvement, just ANCA glomerulonephritis, some prefer the term renal-limited vasculitis. If there is involvement of the respiratory tract or elsewhere with granulomatous inflammation, then Wegener’s granulomatosis is the proper designation if there is no history of asthma. If there is a history of asthma, then Churg-Strauss syndrome. In these patients, the eosinophilia is usually more than 10 percent. If there is no evidence for Wegener’s granulomatosis or Churg-Strauss syndrome, then the term that I would suggest is microscopic polyangiitis. I believe this is preferable to microscopic polyarteritis because many of these patients have no apparent involvement of arteries at all. They may have pulmonary capillaritis, they may have postcapillary venulitis in the skin, they may have glomerulonephritis, but they may not have arteritis. So the term microscopic polyangiitis is a better generic term.ANCA specificities
With respect to the association of the autoantibody specificities, various cohorts have been analyzed. This is an analysis of 111 patients from our cohort of ANCA-diseased patients. There is a predominance of the anti-PR3 specificity in patients with the Wegener’s granulomatosis phenotype, but at least in our experience at this point, about one-third of these patients have anti-MPO specificity. In the microscopic polyangiitis patients, there is about an equal frequency of anti-MPO and anti-PR3 antibodies with possibly a little bit of predominance of anti-MPO specificity. In the patients with renal-limited disease, there is a very striking predilection for the anti-MPO.Chapel Hill nomenclature system
I would suggest that the categorization of small-vessel vasculitis in patients with renal disease can usually be accommodated by what is sometimes referred to as the Chapel Hill nomenclature system, which categorizes some of these major forms of small-vessel vasculitis as Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, all associated with ANCA; Henoch-Schönlein purpura, with IgA dominant immune complexes; cryoglobulinemic vasculitis, with circulating cryoglobulins and cryoglobulins in the tissues; and then occasional patients who have small-vessel vasculitis just confined to the skin. These patients may have a self-limited, benign course, but some of these patients will ultimately be found to have systemic involvement including the kidney.Vasculitides not on the above list
Of course, there are other forms of small-vessel vasculitis not accommodated in this particular list that I’ve described earlier: lupus- associated vasculitis, some forms of drug-induced vasculitis, infection-associated vasculitis. But in all of these circumstances, I think the initial approach should be to recognize that your patient has a small-vessel vasculitis and then as best you can to pursue additional diagnostic procedures, for example immunohistology on biopsy tissue, serology, to put them into a more specific category because that will impact substantially on the appropriate treatment regimen.References
- Godman G, Churg J. Wegener’s granulomatosis. Pathology and review of the literature. Arch Pathol Lab Med 1954;58:533-553.
- Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: The proposal of an international consensus conference. Arthritis Rheum 1994;37:187-192.
- WGET research group. Etanercept plus standard therapy for Wegener’s granulomatosis.
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- Jayne D et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003;349:36-
- Salvarani C et al. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med 2002;347:261-
- Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J Med 2003;349:160-
- Hoffman GS et al. Wegener’s granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488-
- Hoffman GS et al. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002;46:1 309-
- Kallenberg CGM, Brouwer E, Weening JJ, Cohen Tervaert JW: Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiologic potential. Kidney Int 1994,46:1-15.
- Jennette JC, Falk RJ: Anti-neutrophil cytoplasmic autoantibodies: Discovery, specificity, disease associations and pathogenic potential. Adv Pathol Lab Med 1995; 8:363-377
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