An essential early step toward understanding vasculitis was recognition in 1948 of the differences between the small artery disease of polyarteritis, essentially sparing the glomerulus and lungs, and disease of glomerular vessels and small veins, often involving the lungs. By 1951, Churg and Strauss drew on their knowledge of vasculitis literature and renal pathology to provide an authoritative description of the syndrome bearing their names. One year later a paper from Australia described a syndrome of febrile systemic illness with myalgias, arthralgias, microscopic hematuria, and a serum antibody reacting with neutrophil cytoplasm antigens. Within 30 years, nephrologists and immunologists in northern Europe linked antineutrophil cytoplasm antibodies to a specific vasculitis, Wegener’s granulomatosis. Falk and Jennette later determined that pANCA reacted with cytoplasmic myeloperoxidase, and that cANCA did not; the antigen with which cANCA reacted was soon identified as a novel serine proteinase. New and better treatments of AAV will follow progress in understanding their pathogenesis.
Until the discovery of antineutrophil cytoplasm antibodies (ANCA), it had been assumed that most vasculitis resulted from immune complex or antibasement membrane mediation. This article is based on the evidence that ANCA can directly activate neutrophils and monocytes and lead to inflammation of small and medium-sized arteries, capillaries, and venules, hence ANCA-associated vasculitis (AAV). The detection of ANCA is not prima facie evidence of causation of vasculitis, but there is strong empiric evidence for the pathogenicity of MPO-ANCA, if not for PR3-ANCA, as is evident elsewhere in this issue. The reported frequencies of ANCA in the AAV depend on the population and methodology, but for Wegener’s granulomatosis (WG), the frequencies range from 40% to 95% for PR3-ANCA and 5% to 60% for MPO-ANCA. For Churg-Strauss syndrome (CSS), the frequencies range from 30% to 70% for MPO-ANCA or PR3-ANCA, and as much as 75% for MPO-ANCA in microscopic polyangiitis (MPA). Other ANCA are directed against elastase, lactoferrin, azurocidin, lysozyme, H-lamp-2, and other antigens, and are of uncertain significance.
The disorders that are included in the AAV and polyarteritis nodosa spectrum can be difficult to differentiate in individuals. Clinical and objective laboratory and anatomic differences between MPA and classical polyarteritis nodosa (PAN), and MPA and WG are sometimes inconclusive. PAN is not included as an AAV because of its localization to arteries and the usual absence of ANCA. Incidentally, the term microscopic polyangiitis is preferred over microscopic polyarteritis because of the usual absence of arterial lesions in the former; however, both terms are used here to reflect their historical use.
Identification of the three primary ANCA-associated syndromes evolved from comparisons of their anatomic features with those of classical polyarteritis nodosa, which had been described in 1886 and 1908. The kidney was the major focus for many relevant reports from the first half of the 20th century, exemplified by a comprehensive study entitled “The Kidney in Periarteritis Nodosa” by Davson, Ball, and Platt, which established a precedent for separating renal lesions of periarteritis nodosa from those of malignant nephrosclerosis, and suggested the separation of classical periarteritis from microscopic polyarteritis.
Fourteen autopsied cases were divided into two groups, the first with systemic arteritis without aneurysms but with lesions in the lungs and widespread necrotizing glomerulitis. The authors called this microscopic periarteritis and emphasized the necessity of considering this entity in patients with what might otherwise be considered focal embolic nephritis or type 1 nephritis. The second group had systemic arteritis without significant glomerular change or lung lesions and would correspond to today’s PAN. In this, they anticipated the current distinction between PAN, which excludes glomerulonephritis or vasculitis in arterioles, capillaries or venules, and microscopic polyarteritis with vasculitis affecting small vessels including capillaries, venules, and arterioles. They also stressed that cases with renal failure or hypertension occurring in a pyrexial illness should be suspect for periarteritis. The first group appeared to be compatible with what is today called microscopic polyangiitis. Davson’s view of the glomerulus as a specialized blood vessel was explicit in a later paper. Zeek also suggested that there were two distinct types of periarteritis: hypersensitivity angiitis with glomerulonephritis and true periarteritis.
In 1985, Savage and colleagues described the presentation, pathology, and prognosis of what they termed microscopic polyarteritis, based on studies of 34 patients. Their definition required clinical or histologic evidence of small vessel systemic vasculitis associated with focal segmental necrotizing glomerulonephritis for which there was no other explanation; this corresponds to the definition now in use for MPA. The predominating symptoms were fever, arthralgia, cutaneous purpura, hemoptysis or pulmonary hemorrhage, abdominal pain, mouth ulcers, and sensory neuropathy. Laboratory findings included anemia, elevated creatinine, and microscopic hematuria in all patients, and proteinuria in excess of 3 g in 41% of patients. Seven had definite alveolar hemorrhage, and it was suspected in three others. Visceral arteriograms, done in 12 patients to exclude PAN, were normal. Focal segmental necrotizing glomerulonephritis was found in all renal specimens from 32 patients, and crescents were found in 88% of patients. Of note, granular glomerular immunoglobulin deposits were found by direct immunofluorescence in only a few of 20 specimens. This is an example of pauci-immune glomerulonephritis, which is included often in the definition of the renal disease found in AAV. Small-vessel vasculitis with fibrinoid necrosis was found in five of nine skin biopsies. The patients were treated with varying regimens of glucocorticoids and immunosuppressive drugs, and the actuarial survival rate at 1 year was 70%. The authors compared microscopic polyarteritis with WG, PAN, and CSS, convincingly establishing its singularity.
Fourteen years later and in the era of ANCA, Guillevin and other members of the French Vasculitis Study Group published an analysis of the clinical and laboratory features of 85 MPA patients, of whom 81 were biopsy-proven. They were similar to those of Savage, the dominant symptoms being weight loss, rash, fever, neuropathy, arthralgias, and myalgias. A large number (17.6%) had heart failure. Serum creatinine was elevated in 47 patients. Microaneurysms were seen by angiography in 4 of 30 patients who were examined. ANCA were found in 38 of 51 patients; in 33 this was pANCA and in 5, cANCA. Four patients had PR3-ANCA, and 31 had MPO-ANCA. The 5-year survival rate of 74% was better in patients treated with glucocorticoids and immunosuppressive drugs than those treated with glucocorticoids alone.
Klinger, writing in 1931, is thought to have authored the first description of what is now termed WG. Of Klinger’s description, Wegener wrote that it depicted a man with a borderline form of polyarteritis nodosa and severe nasal changes. In the late 1930s, Wegener established the disease as a distinct entity thought to be most likely an allergic reaction to infection. A short paper entitled “On Generalized Septic Vessel Diseases,” identified the major characteristics of the disease as a septic course, with extremely severe necrotizing granulomatous inflammation of the inner nose, pharynx, and larynx; localized glomerulonephritis; and generalized arteritis with the picture of periarteritis nodosa. Godman and Churg described the features of WG more fully, and concluded that it and microscopic polyarteritis and CSS were related through a similar pathogenesis involving hypersensitivity. In the same year, a major clinical study of WG was published, by which time 18 autopsied cases had been reported, to which six more were added, plus one patient still living after 19 months of cortisone or corticotropin (ACTH). The authors, Jacob Churg among them, confirmed the three characteristic anatomic features that Godman and Churg had identified:
Necrotizing granulomatous lesions in the upper or lower respiratory tract
Generalized focal necrotizing vasculitis involving both arteries and veins and almost always present in the lungs
Glomerulitis comprising necrosis and thrombosis of loops of the capillary tuft and evolution as a granulomatous lesion.
They acknowledged the similarity to what is now termed Churg-Strauss vasculitis, but felt that WG can be distinguished on the basis of marked predominance of necrotizing granulomatous lesions in the respiratory tract, the regular occurrence and severity of the renal lesions, and the usual absence of allergy or tissue eosinophilia.
An influential paper by Fauci and Wolff reviewed the clinical and laboratory features of 18 patients with WG who had been studied during the 12 years before its publication in 1973. They built upon their earlier pioneering studies of cyclophosphamide in this disease, and in so doing, further rationalized its use, thereby altering the prognosis from relentless morbidity and death to remission. Their guidelines for the use of glucocorticoids and cyclophosphamide still determine or influence the treatment of this disease and others. Investigations of immunologic markers by Shillitoe and colleagues, which included tests for autoantibodies to thyroid, gastric cells, adrenal, smooth muscle, DNA, mitochondria, and reticulin in 10 patients were negative, as were tests for rheumatoid factors and immune complexes, and they felt confident to dismiss circulating immune complexes as major players in the etiology of WG. Searches for infectious causes of WG have been considered fruitless, although it is thought that Staphylococcus aureus might be associated both with onset of disease and relapses. A putative relationship between S aureus and other infectious agents has been reviewed recently, and there is persisting interest in the use of trimethoprim-sulfamethoxazole popularized by DeRemee and others for the prevention of relapse. Unlike infections, drugs have been clearly implicated as causes of ANCA-positive vasculitis syndromes, including WG, which often subside after withdrawal of the drug. Choi and colleagues described 30 patients with exposures to drugs including hydralazine and propythiouracil whose vasculitis was associated with anti-MPO titers more than 12 times the median of 250 patients. Ninety-two patients in Japan with MPO-ANCA associated vasculitis who had taken methimazole or propylthiouracil were reported to a firm marketing antithyroid drugs. Forty-one of the 92 had single-organ failure; 32 had double-organ failure. Thirteen had triple-organ failure and in two, there was quadruple-organ failure. The median time of onset of symptoms after starting drug treatment was 42 months, with a range of 1 to 372 months. The severity or number of involved organs did not correlate with the MPO-ANCA titer, suggesting to the investigators a need for vigilance even among patients with low titers.
The significance of a five-paragraph report from Australia entitled “Segmental Necrotising Glomerulonephritis with Antineutrophil Antibody: Possible Arbovirus Etiology?” was not recognized at the time of its publication in 1982. It described eight patients who had arthralgias and myalgias, anorexia, vomiting and diarrhea, and microscopic hematuria. Five had abnormal chest radiographs, and renal biopsies showed segmental necrotizing glomerulonephritis with frequent crescents. All patients had a factor in their serum that stained the cytoplasm of neutrophil leucocytes by indirect immunofluorescence; similar staining had not been seen in more than 5000 sera examined in the preceding 5 years. The glomerular lesions were morphologically identical to those of microscopic polyarteritis, referring to the criteria elaborated by Davson in the study mentioned earlier. Although the authors mused over the possibility that the illness was caused by Ross River virus, the patients had been treated by their clinicians with a regimen of prednisone and cyclophosphamide or azathioprine.
Within 2 years, a different Australian group cited this report, and added four patients who had malaise, arthralgia, and pulmonary involvement; two had a rash due to vasculitis, and three had active urinary sediment and segmental necrotizing lesions on kidney biopsy. All four had cytoplasmic staining of neutrophils on immunofluorescence examination. The investigators thought this represented a homogenous illness “loosely labeled arteritis,” for which treatment with steroids and cytotoxics was encouraged.
In 1985, nephrologists and immunologists from the Netherlands and Denmark published the first of what would be many studies identifying ANCA in WG, and by extrapolation, other polyarteritis syndromes. The authors were seasoned investigators whose previous work had centered on glomerulonephritis and vasculitis, and the laboratory assessment of indicators of immunologic disease. They studied 41 patients with biopsy-proven WG, finding ACPA (an early designation for ANCA) by indirect immunofluorescence in 25 of 27 patients with active disease and 4 of 32 with inactive disease. They rather prematurely concluded that the autoantibody was specific for WG. In this regard, it was fortuitous that ANCA were not found among their control patients, of whom 15 had tuberculosis (in which ANCA have been repeatedly identified) and 14 had “various forms of small-vessel vasculitis.” Inasmuch as 33 of the controls were said to have classical polyarteritis, it is surprising that ANCA were not found among the 14 with small vessel disease, which they differentiated from polyarteritis.
Falk and Jennette studied sera from seven patients with WG and three with microscopic polyarteritis, and from 35 persons with idiopathic necrotizing and crescentic glomerulonephritis, 11 with lupus nephritis and 71 with other renal lesions. On indirect immunofluorescence (IIF) microscopy, they found two different staining patterns of ANCA: diffuse granular staining with accentuation near the center, and perinuclear to nuclear depending upon the method used for preparing the neutrophils. None of the 50 blood bank sera controls were positive for ANCA; however, positive reactions were found in significant titers in sera representing necrotizing and crescentic glomerulonephritis but not in lupus and other renal lesions. They concluded from the IIF and enzyme-linked immunosorbent assay (ELISA) that ANCA were found in patients with necrotizing and crescentic glomerulonephritis whose clinical disease ranged from kidney-limited to overt vasculitis including WG and polyarteritis. ANCA associated with the necrotizing and crescentic glomerulonephritis were specific for constituents of neutrophil primary granules, and there were at least two types of antibodies. Some produced perinuclear staining of alcohol-fixed neutrophils that reacted with myeloperoxidase (pANCA), and others produced diffuse cytoplasmic immunostaining not due to myeloperoxidase (cANCA). These important discoveries have inspired much of the later ANCA research.
In the following year, in a study of sera producing cytoplasmic staining in 10 patients with WG, Niles and colleagues identified the antigen to which cANCA reacts as a novel serine proteinase. The antigen was distinct from neutral proteases elastase and cathepsin G, and they surmised that it might be proteinase 3. Confirmation of this came from Ludemann, Utecht, and Gross, who identified the antigen as an elastinolytic enzyme. Shortly thereafter they revised the antigen’s nucleotide and amino acid sequence that they had published earlier. Sera from 277 patients with WG and 1657 controls were analyzed for ACPA (ANCA) by IIF and ELISA in 1989. The specificity for WG among the sera was 99% by IIF and 98% by ELISA, and sensitivity depended on extent and activity of the disease. For example, it was 67% by IIF for patients with active but localized symptoms, and for patients in full remission, the sensitivity by IIF was 41%. The investigators concluded, as did others, that APCA could be used as a marker to follow disease activity.
By 1990, the authors of the 1982 report that had first described ANCA in patients with vasculitis and glomerulonephritis had screened 7500 sera for ANCA by IIF, finding it in 17. Eleven of the patients with ANCA were diagnosed with microscopic polyarteritis based on small vessel disease with focal segmental glomerulonephritis without evidence of WG, and four patients with WG. Remissions were induced in all patients who were treated with prednisolone and cyclophosphamide, and tests for ANCA became negative except in three patients thought to have MPA. There were five relapses, with return of ANCA positivity in patients who had been ANCA negative. Anticipating questions about the relationship between ANCA and activity of vasculitis, the authors specifically noted that ANCA were a sensitive but not specific marker of disease relapse, but also that ANCA persisted in three patients even though there was no clinical evidence of disease activity. They also noted the absence of ANCA by IIF in 15 patients with active MPA or WG, but they did not relate its presence or absence to extent of disease, as others had.
Boomsma and colleagues studied 100 patients with WG from 1996 to 1998, and obtained serum samples for ANCA analysis every 2 months. During this time, relapses occurred in 37 patients; of these, 34 showed a rise in the level of ANCA preceding the relapse. The predictive value for relapse was greater for increases in cANCA determined by ELISA than by IIF. In 29% of patients, the rise in ANCA titers was not followed by a relapse during an extended observation, and only 39% had a relapse within 6 months. They therefore cautioned against starting or escalating immunosuppressive therapy based solely on ANCA levels.
Periarteritis was linked with asthma in a prescient 1939 account by Rackemann and Greene of eight persons with severe asthma, pain and numbness in the extremities, and eosinophilia. The index case was a 36-year-old woman, who for 3 years had nasal stuffiness, rhinitis, and for 6 months cough and mild attacks of wheezing. Her leukocyte count was about 18,000/mm 3 with 30% to 40% eosinophils. Antemortem diagnoses were tuberculosis, lupus erythematosus and, finally, periarteritis nodosa. At autopsy, there was extensive pericarditis, enlargement of the heart, and “lesions of periarteritis nodosa” in many organs. “Tremendous eosinophilia” was “the important feature” in each of the eight cases. Including their own, 27 cases were reviewed; 19 had both asthma and periarteritis nodosa. Increased eosinophils were counted in 74%, and this triad was regarded as virtually diagnostic of a polyarteritis syndrome. Their next steps were to learn what periarteritis nodosa is and determine the functions of the eosinophil, still worthy goals.
This description of the triad of asthma, periarteritis, and eosinophilia was acknowledged by Churg and Strauss in their monograph entitled “Allergic Granulomatosis, Allergic angiitis, and Periarteritis nodosa.” In it, they reviewed the clinical histories of 13 patients with asthma, fever, and pneumonia; central and peripheral neuropathy; skin rashes including purpura and nodules; mild generalized lymphadenopathy; arthralgias; and mild hematuria and proteinuria. The anatomic changes they described so carefully and illustrated with clear photographs were widespread vascular lesions like those of periarteritis; “tissue alteration” comprising eosinophilic necrosis; fibrinoid collagen, and granulomatous proliferation of epithelioid and giant cells termed “allergic granuloma.” The granuloma within vessel walls and connective tissue throughout the body differed from lesions of classical periarteritis, which they knew well. The most characteristic lesions were granulomatous nodules associated with inflammation within and near small vessel walls. Small dense aggregates of eosinophils were observed along with macrophages around a focus with the appearance and radial arrangement of epithelioid cells. Lesions in blood vessels in 9 of 10 autopsied cases were similar to those seen in periarteritis nodosa except for the granulomatous lesions, which distinguished them from periarteritis. All stages of arteritis were seen, including aneurysms, although healed fibrosed lesions predominated. The epicardium was the most common seat of granulomatous nodules, which were found in 6 of 10 autopsied cases. Branches of pulmonary arteries were involved, and lung lesions suggested pneumonia with eosinophils and giant cells. Focal glomerular lesions involved a few capillary loops. Cutaneous nodules were of great diagnostic importance.
They noted that their findings were in agreement with those of Wilson and Alexander, who in their review of 300 published cases of periarteritis nodosa found that high eosinophilia was present in 94% of the cases associated with asthma and in only 6% of those without a history of asthma. Churg and Strauss concluded that there were valid clinical and anatomic reasons for defining their symptom complex as allergic angiitis and allergic granulomatosis. Its allergic etiology was clearly proved, at least as long as asthma is considered an allergic disease. The clinical manifestations of CSS were recognized as highly variable.
An authoritative explication of the syndrome now bearing their names was possible because of their knowledge of the literature pertaining to vasculitis and their expertise in renal and vascular pathology. They were both pathologists at Mount Sinai Hospital in New York City, and two of a distinguished group that has been memorialized in that institution’s Hall of Fame. Incidentally, six of them are remembered in eponymic syndromes. Dr Churg was especially expert in renal pathology as other vasculitis investigators have been, and he published more than 300 papers during his career at Mount Sinai. Dr Strauss was also a prolific investigator and author of about 100 scientific papers. She was interested in vascular and uterine diseases, and she is regarded as the founder of pediatric pathology. The rapidly evolving ANCA paradigm promises to explain certain phenomena of the immune systems, and to provide targeted treatment of AAV.