Correlation of antineutrophil cytoplasmic antibodies with the extrarenal histopathology of Wegener's (pathergic) granulomatosis and related forms of vasculitis.

We studied the histologic findings from extrarenal biopsies (especially of the lung or upper respiratory tract) or autopsies of 68 patients who were tested for serum antineutrophil cytoplasmic antibodies (ANCAs). We used antigen-specific assays to detect antibodies against proteinase 3 (PR3) and myeloperoxidase (MPO), the two types of ANCAs of proven diagnostic value for the spectrum of diseases that includes Wegener's (pathergic) granulomatosis, microscopic polyarteritis (microscopic polyangiitis), Churg-Strauss syndrome, idiopathic necrotizing and crescentic glomerulonephritis, and their variants. Twenty-eight patients had antibodies to PR3 and 16 had antibodies to MPO; no patient had antibodies to both. All 44 patients with ANCAs had histologic evidence of this spectrum of diseases. Thirteen patients without histologic evidence of this spectrum of diseases had negative tests for ANCAs. There were no pathologic features that reliably identified patients with one or the other type of ANCA. Eighteen of 31 patients with lesions of Wegener's granulomatosis had antibodies to PR3, seven had antibodies to MPO, and six had neither. Three of four patients with necrotizing arteries without granulomas had anti-MPO antibodies, but similar lesions were seen, together with extravascular granulomas, in three patients with anti-PR3 antibodies. Of 16 patients with alveolar hemorrhage, nine had anti-PR3 and five had anti-MPO antibodies. Two patients diagnosed clinically as having Churg-Strauss syndrome had anti-MPO antibodies. In 16 of the 25 patients with ANCAs and a histologic diagnosis of Wegener's granulomatosis the diagnosis was made on the basis of extravascular granulomatous lesions alone, which argues against the requirement for vasculitis. Of six patients with negative tests for ANCAs and histologically diagnosed Wegener's granulomatosis, none had evidence of renal involvement. We conclude that in the appropriate clinical setting the presence of anti-PR3 or anti-MPO antibodies provides reliable evidence of the above spectrum of diseases, but that subclassification (to the extent this is possible) depends on the presence of distinctive clinical or pathologic features. In patients with negative tests for ANCAs, interpretation of clinical and histologic findings remains the only definitive method of diagnosis.

Clinical utility of fine needle aspiration biopsy in the diagnosis of Wegener's granulomatosis. A report of two cases.

In two patients, pulmonary lesions of Wegener's granulomatosis (WG) were sampled by fine needle aspiration biopsy: one with the clinical diagnosis of primary pulmonary malignancy and the other with a clinical suspicion of WG. In the latter case the smears showed distinctive eosinophilic, collagen necrosis (pathergic necrosis), poorly formed granulomata composed of loose aggregates of elongated, often palisading epithelioid histiocytes, and multinucleate histiocytes. A cell block preparation in this case contained minute tissue fragments illustrating the distinctive, pathergic-type necrosis. In the former case, many of these features were present, but additionally there were several groups, atypical bronchial epithelial cells that, in light of the clinical impression, initially led to an incorrect diagnosis of bronchoalveolar carcinoma. Subsequent review of this case led to the diagnosis of WG. Antineutrophil cytoplasmic antibody (ANCA) serology was later obtained, confirming the diagnosis of WG in both cases. In our experience, the cytomorphologic findings of granular collagen necrosis, granulomata and multinucleate cells, although not specific, should alert the cytopathologist to consider the diagnosis of WG, especially when special stains for microorganisms are negative. A recommendation for ANCA serology testing early in the disease process, particularly in the limited forms of the disease, may lead to early recognition of WG, resulting in prompt institution of immunosuppressive therapy, greatly improving the patient's prognosis.

Antigen-specific radioimmunoassays for anti-neutrophil cytoplasmic antibodies in the diagnosis of rapidly progressive glomerulonephritis.

Circulating anti-neutrophil cytoplasmic antibodies (ANCA) have been described in most patients with "pauci-immune" necrotizing and crescentic glomerulonephritis. A 29-kDa serine protease (p29 or proteinase 3) and myeloperoxidase are the two best characterized antigens recognized by ANCA. The study presented here was conducted to define the diagnostic value of assays for antibodies against these two antigens in rapidly progressive glomerulonephritis. Radioimmunoassays were developed for anti-p29 and anti-myeloperoxidase antibodies, with purified antigens, and the results of the radioimmunoassays were compared with those obtained by immunofluorescence tests for ANCA. We performed assays on serum samples from 123 patients with the syndrome of rapidly progressive glomerulonephritis, as well as from 200 blood bank donors and from 717 additional control patients. Without knowledge of the results of ANCA tests, the renal pathologic findings in the 123 patients with rapidly progressive glomerulonephritis were analyzed, and 42 were classified as pauci-immune necrotizing and crescentic glomerulonephritis, 18 were classified as anti-glomerular basement membrane nephritis and 63 were classified as other forms of renal disease. We found radioimmunoassays to be more reliable in the diagnosis of pauci-immune necrotizing and crescentic glomerulonephritis than immunofluorescence testing. By radioimmunoassay, ANCA were found in 40 of 42 patients (95% sensitivity) with pauci-immune necrotizing and crescentic glomerulonephritis (14 with anti-p29 and 26 with anti-myeloperoxidase antibodies). The tests for antibodies to p29 and myeloperoxidase were 99.9 and 99.5% specific for pauci-immune necrotizing and crescentic glomerulonephritis, respectively. In the setting of rapidly progressive glomerulonephritis, a positive radioimmunoassay for anti-p29 or anti-myeloperoxidase antibodies (together with a negative test for anti-GBM antibodies) gives a probability of pauci-immune necrotizing and crescentic glomerulonephritis of over 99%.

The pulmonary biopsy in the early diagnosis of Wegener's (pathergic) granulomatosis: a study based on 35 open lung biopsies.

We reviewed open lung biopsies from 35 patients with Wegener's (pathergic) granulomatosis in order to study the histogenesis of the pulmonary lesions and to identify the early lesions. The process of pathergic necrosis is fundamental in the production of extravascular and vascular lesions and was divided into micronecrotic and macronecrotic types. Micronecrosis, usually with neutrophils (microabscesses), constitutes the early phase in the development of the pathognomonic organized palisading granuloma. The palisading granuloma differs from the compact granuloma of tuberculoid type, which occurs in infections and sarcoidosis but not in Wegener's (pathergic) granulomatosis. There is a progression of disease from micronecrosis to macronecrosis (widespread necrosis) and then to fibrosis. Macronecrosis surrounded by palisading histiocytes or diffuse granulomatous tissue indicates active disease, whereas necrosis surrounded by fibrous tissue indicates previously active disease. Most cases have a combination of micronecrosis, and fibrosis. We established the relative diagnostic value of various histologic features. Arteritis and phlebitis as classically described in Wegener's granulomatosis were present in most but not all cases. We believe that Wegener's granulomatosis primarily affects both vascular and extravascular collagen and reticulum and that vasculitis represents a primary necrosis of walls of blood vessels. We believe that the concept of Wegener's granulomatosis as a vasculitis is too restrictive and does not include many cases with only extravascular histologic changes.

Vasculitis in primary vasculitides, granulomatoses, and connective tissue diseases.

Problems with the classification and diagnosis of vasculitides are discussed. The evidence related to the pathogenetic importance of immune complexes in vasculitis, both in experimental models and human disease, is reviewed. The finding, by immunofluorescence, of immunoglobulins and complement components in vessel walls has provided indirect evidence of a role of immune complexes in certain forms of human vasculitis. However, specific antigens have been demonstrated in very few instances, notably in some patients with hepatitis B infection. In most forms of human vasculitis there is no information about causative factors. The widely held belief that therapeutic drugs cause an appreciable proportion of cases of human vasculitis appears unfounded.

The protracted superficial phenomenon in pathergic (Wegener's) granulomatosis.

Twelve cases of pathergic (Wegener's) granulomatosis are described, with special attention focused on the long duration of mucosal and skin lesions in untreated cases, designated as the protracted superficial phenomenon, and on the histologic features that may be helpful in making the diagnosis. The long duration, often the result of a lack of proper interpretation of histologic details, was associated in some of the cases studied with the development of intractable renal failure or mutilation of the face. Since cytotoxic therapy offers the opportunity to prevent these complications, the desirability of an early diagnosis is obvious. Biopsy is the principal means of diagnosis, and therefore interpretation of histologic details is of paramount importance. Helpful histologic features found in the extravascular and vascular tissues of the specimens studed were focal necrosis, fibrinoid degeneration, palisading granulomas, giant cells, and vasculitis. Nonpalisading foci of granular necrosis or fibrinoid degeneration appeared to precede the development of the typical palisading granuloma. Both focal necrosis and focal fibrinoid degeneration occurred independently of intrinsic vascular involvement and in themselves are distinctive features of pathergic (Wegener's) granulomatosis. There was predominance of the extravascular components in the cases studied with occasional absence of vasculitis. Both the extravascular and vascular components are important in making a definitive diagnosis, but the extravascular component is characteristic, even in the absence of vasculitis. The extravascular tissues and the vessels are parallel contemporaneous target tissues.