REVIEW

Wegener Granulomatosis: An Analysis of 158 Patients Gary S. Hoffman, MD; Gail S. Kerr, MD; Randi Y. Leavitt, MD, PhD; Claire W. Hallahan, MS; Robert S. Lebovics, MD; William D. Travis, MD; Menachem Rottem, MD; and Anthony S. Fauci, MD

• Objective: To prospectively study the clinical features, pathophysiology, treatment, and prognosis of Wegener granulomatosis. • Design: Of the 180 patients with Wegener granulomatosis referred to the National Institute of Allergy and Infectious Diseases during the past 24 years, 158 have been followed for 6 months to 24 years (a total of 1229 patient-years). • Measurements: Characteristics of clinical presentation, surgical pathology, course of illness, laboratory and radiographic findings, and the results of medical and surgical treatment have been recorded in a computer-based information retrieval system. • Setting: The Warren Magnuson Clinical Center of the National Institutes of Health. • Main Results: Men and women were equally represented; 97% of patients were white, and 85% were more than 19 years of age. The mean period of follow-up was 8 years. One hundred and thirty-three patients (84%) received "standard" therapy with daily low-dose cyclophosphamide and glucocorticoids. Eight (5.0%) received only low-dose cyclophosphamide. Six (4.0%) never received cyclophosphamide and were treated with other cytotoxic agents and glucocorticoids. Ten patients (6.0%) were treated with only glucocorticoids. Ninety-one percent of patients experienced marked improvement, and 75% achieved complete remission. Fifty percent of remissions were associated with one or more relapses. Of 99 patients followed for > 5 years, 44% had remissions of > 5 years duration. Thirteen percent of patients died of Wegener granulomatosis, treatment-related causes, or both. Almost all patients had serious morbidity from irreversible features of their disease (86%) or side effects of treatment (42%). • Conclusions: The course of Wegener granulomatosis has been dramatically improved by daily treatment with cyclophosphamide and glucocorticoids. Nonetheless, disease- and treatment-related morbidity is often profound. Alternative forms of therapy have not yet achieved the high rates of remission induction and successful maintenance that have been reported with daily cyclophosphamide treatment. Despite continued therapeutic success with cyclophosphamide, our longterm follow-up of patients with Wegener granulomatosis has led to increasing concerns about toxicity resulting from prolonged cyclophosphamide therapy and has encouraged investigation of other therapeutic regimens. Annals of Internal Medicine. 1992;116:488-498. From the National Institutes of Health, Bethesda, Maryland. For current author addresses, see end of text. 488

W egener granulomatosis is distinguished from other necrotizing vasculitides by its predilection to affect the upper and lower respiratory tracts and, in most cases, the kidneys. Inflammatory lesions typically include necrosis, granulomatous changes, and vasculitis (1-7). Relatively mild forms of disease without renal involvement have been previously described. The course of illness in such patients may vary from indolence to rapid progression. However, most patients with untreated or ineffectively treated generalized disease (including glomerulonephritis) experience a rapidly progressive, fatal illness (7, 8). In prospective studies (5, 6) we have shown that Wegener granulomatosis could be effectively treated using low-dose daily cyclophosphamide and glucocorticoids. These observations have been confirmed by other investigators (9). The National Institutes of Health (NIH) experience has grown to include 180 patients with Wegener granulomatosis. Adequate follow-up to characterize disease and treatment was available for 158 of these patients. Although treatment has been life-saving, extended follow-up has led to recognition of a greater frequency of disease relapse, morbidity, and drug toxicity than had been previously recognized.

Methods Enrollment of patients in the NIH protocol required a clinical history that was compatible with Wegener granulomatosis and histopathologic evidence of either vasculitis or granulomatous changes in a typical organ system. Cultures and special stains for bacteria, fungi, and mycobacteria were obtained from all nonrenal biopsy samples and appropriate body fluids to rule out infectious granulomatous processes. Treatment Protocol The protocol treatment regimen has been previously described (6). In brief, the regimen consisted of daily, oral therapy with cyclophosphamide, 2 mg/kg body weight, and prednisone, 1 mg/kg body weight. Several patients with fulminant and rapidly progressive disease received 3 to 5 mg/kg of cyclophosphamide daily. We used the leukocyte count to guide subsequent dosage adjustments in these patients. Under these circumstances, prednisone (or a soluble parenteral equivalent) was usually given for the first few days at a daily dose that varied from 2 to 15 mg/kg. Daily prednisone therapy was continued for approximately 4 weeks and then changed over 1 to 3 months to 60 mg on alternate days. The dose was tapered gradually until the patient no longer received prednisone and was maintained solely on cyclophosphamide. The duration of alternate-day prednisone therapy varied according to individual responses to therapy. Cyclophosphamide was continued for at least 1 year after the patient achieved complete remission. Cyclophosphamide was then tapered by 25-mg decrements every 2 to 3 months until discontinuation or until disease recurrence required a dose increase.

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Figure l. Time from onset of Wegener granulomatosis to diagnosis. Patients with limited disease, without renal involvement or severe lung disease, may have an indolent course. Such atypical presentations may result in marked delay in diagnosis.

Criteria for Remission Partial remission was defined as clear-cut suppression of disease with stabilization of renal function and at least partial resolution of pulmonary infiltrates. Further, other organ system disease was required to show signs of improvement to be classified as a partial remission. Criteria for complete remission included the absence of evidence of active disease, complete resolution of pulmonary infiltrates or evidence of stable scarring without signs of active inflammation, absence of systemic inflammatory disease such as serositis and fever, and stabilization or improvement in renal function with no further evidence of active renal sediment. Minor abnormalities of urine sediment, compatible with previous glomerular damage, were present in some patients who achieved a complete remission.

Results Patient Sample Although our previously reported experience suggested a slight male predominance (6), our larger sample of 158 patients included equal numbers of men and women. Of these patients, 97% were white, 2% were black, and l% were of other racial backgrounds. The mean age was 41 years (range, 9 to 78 years), and 15% of patients were less than 19 years of age. Presenting Features of Disease The median and mean periods from the onset of symptoms to a diagnosis of Wegener granulomatosis were 4.7 and 15 months, respectively. In some cases, the correct diagnosis was apparent at the first physician visit. The diagnosis of Wegener granulomatosis was made within 3 months of symptom onset in 42% of patients, but in 8% of patients the diagnosis was not made until 5 to 16 years later. Patients in this latter group had indolent progression of mild disease that led to delays in diagnosis. Inclusion of these patients accounts for the large variation between the mean and the median (Figure 1). The signs and symptoms of Wegener granulomatosis that were present at disease onset and during the course of illness are shown in Figures 2 and 3. Most patients first sought medical care because of upper or lower airway symptoms or both (90%). Nasal, sinus, tracheal (upper airway), or ear abnormalities were initially re-

sponsible for symptoms in 73% of patients and occurred in 92% of patients overall (Figure 2 and Figure 3, top left). In the absence of systemic illness, these problems were often considered to be secondary to allergy or infection. Symptomatic treatment, followed by persistent symptoms and complications, especially recurrent epistaxis, mucosal ulcerations, nasal septal perforation, or nasal deformity, led in some cases to more extensive evaluation. The findings of an active urine sediment, pulmonary infiltrates or nodules, elevated erythrocyte sedimentation rates, unexplained anemia, and, in recent years, antineutrophil cytoplasmic antibodies (ANCA) prompted some referring physicians to pursue definitive diagnosis by biopsy of the involved organs. In 30% of cases, the absence of rigorous pursuit of diagnosis, the lack of symptomatic pulmonary and renal findings, or the indolent course of illness led to delays in diagnosis greater than 1 year. Pulmonary infiltrates, nodules, or both were initially present in 45% of patients (Figure 3, top right, and Figure 4). Symptoms included cough (19%), hemoptysis (12%), and pleuritis (10%). During the entire course of illness, 66% of all episodes (241) of Wegener granulomatosis were associated with either cough (46%), hemoptysis (30%), and/or pleuritis (28%). In about 34% of cases radiographs showed infiltrates or nodules that were asymptomatic. Eighty-five percent of patients eventually developed lung disease related to Wegener granulomatosis. As previously reported (6), several patients (18%) presented with features of glomerulonephritis (see Figure 2); in all such cases renal disease was asymptomatic. Seventy-seven percent of patients later developed glomerulonephritis, usually within the first 2 years of disease onset. Ocular abnormalities were noted in 15% of patients (see Figure 2 and Figure 3, bottom left) during the early phases of Wegener granulomatosis and in most cases produced significant symptoms. Fifty-two percent of patients eventually developed one or more features of eye disease, which, in general, were nonspecific. The most diagnostically helpful ocular finding was proptosis, which, when present in the setting of upper or lower airway disease or glomerulonephritis, was strongly suggestive of Wegener granulomatosis. Proptosis was present in 2% of patients at disease onset and in 15% at

Figure 2. Major organ systems affected by Wegener granulomatosis. ENT = ear, nose, and throat involvement.

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Figure 3. Type and frequency of disease manifestations are represented at the time of presentation and as they may have occurred during the course of illness. ENT = ear, nose, and throat involvement.

some time during the course of illness. Proptosis was usually painful (Figure 5). About half of the patients with retro-orbital pseudotumors lost vision due to optic nerve ischemia. Entrapment of extraocular muscles also led to loss of conjugate gaze that caused diplopia. Other Manifestations Musculoskeletal symptoms were a prominent feature of disease in 67% of patients. Most patients experienced only arthralgias or myalgias. In patients with persistent or recurrent musculoskeletal symptoms, the differential diagnosis was perplexing. In several cases symmetrical involvement of small and large joints, in conjunction with false-positive test results for rheumatoid factor (60%), led to the incorrect diagnosis of rheumatoid arthritis. In several patients monarticular disease needed to be distinguished from microcrystalline and septic arthritis. Other patients had pauciarticular or migratory polyarthritis. In no instance did deformity occur. For some patients in whom musculoskeletal symptoms were the main initial feature of disease, the diagnosis of Wegener granulomatosis was not made until other, more classic features of illness were present. Fever due to Wegener granulomatosis was initially present in 23% of patients and occurred in 50% during the course of illness. In all cases, the presence of fever led to an evaluation for secondary infection. Significant weight loss, defined as a loss greater than 10% of usual body weight, occurred in 15% of patients at disease onset and in 35% of patients overall. When weight loss was present initially in conjunction with persistent fever, patients had frequently been evaluated by referring physicians for occult malignancy before a diagnosis of Wegener granulomatosis was made. Skin disease occurred in 13% of patients initially and in 46% of patients overall. Lesions included palpable purpura, ulcers, vesicles, papules, and subcutaneous nodules. 490

Nervous system involvement was rare at initial presentation, but mononeuritis multiplex developed eventually in 15% of patients, and central nervous system abnormalities occurred in 8% of patients. The latter included stroke, cranial nerve abnormalities, and one case of diabetes insipidus. Ten (6%) patients developed pericarditis. In eight patients, pericarditis was symptomatic. In one patient, hemodynamic compromise required pericardiocentesis and pericardiectomy. Cardiac muscle or vessel involvement unequivocally due to Wegener granulomatosis was uncommon (< 2% of patients). Biopsy-proven Wegener granulomatosis was noted rarely (< 1% of patients) in the parotid gland, pulmonary artery, breast, urethra, cervix, and vagina. Laboratory Data Sera from 106 patients with Wegener granulomatosis, 40 healthy controls, and 70 patients with disease other

Figure 4. Wegener granulomatosis lung disease may be unilateral or bilateral and may consist of infiltrates, nodules, hemorrhage, or a combination of abnormalities. The right lung field (left) seen in the computed axial tomographic scan in this patient includes an example of coalescent nodules.

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Figure 5. Optic and retro-orbital manifestations of Wegener granulomatosis. Left. Retro-orbital pseudotumor has resulted in proptosis; the position of the left eye is fixed and unable to deviate in conjunction with the right eye. Right, top. A computed axial tomographic scan of the orbits shows entrapment (arrow) of the medial and inferior rectus muscles, as well as impingement on the optic nerve. Right, bottom. In a similar patient, a computed axial tomographic scan shows complete filling of the retro-orbital space with inflammatory-fibrotic tissue that caused blindness. The extent to which fibrous tissue has filled the retro-orbital space is a major determinant of visual outcome after immunosuppressive treatment. than Wegener granulomatosis were tested using indirect immunofluorescence (10) for the presence of ANCA. Leukocytes from normal volunteers were placed on glass slides and fixed in 95% ethanol. Sera from 88% of patients with active Wegener granulomatosis and 43% of patients in remission produced diffuse granular cytoplasmic (C-ANCA) immunofluorescent staining of neutrophils. The difference in positive results between patients with active disease and those in remission was significant (P = 0.008, Fisher exact test). Among patients with active disease, however, no significant differences in test results were noted between treated and untreated patients. Sera from five patients (5%) produced perinuclear (P-ANCA) immunofluorescent staining, which is not a useful diagnostic tool for Wegener granulomatosis. The C-ANCA findings are similar to those previously reported (11-13), in which about 40% of patients in remission and > 90% of patients with active Wegener granulomatosis had positive test results. None of the ANCA studies in the 40 normal controls, 13 patients with polyarteritis nodosa, 21 with idiopathic inflammatory lung disease, 12 with uveitis, 2 with systemic lupus erythematosis, or 2 with polymyositis showed granular cytoplasmic staining. One of 12 patients with Takayasu disease, 1 of 3 with lymphomatoid granulomatosis, and 1 patient with isolated cutaneous vasculitis had positive C-ANCA results at a

low titer (< 1:80). Sera from one patient each with polyarteritis nodosa, uveitis, and polymyositis produced a P-ANCA pattern. In a previous study, Cohen Tervaert and colleagues (14) suggested that in stable patients with Wegener granulomatosis, a rise in C-ANCA titer usually portends a clinical exacerbation. Although some investigators feel that this association justifies increased immunosuppressive therapy, we feel that such measures may be premature. The sample in this study was small (20 patients), and about half of the patients who had an asymptomatic rise in C-ANCA experienced delays in clinical exacerbation of 1 to 2 years. Currently, it seems more prudent to simply follow more closely those patients with such isolated serologic changes. Before initiation of therapy, patients with active Wegener granulomatosis often had leukocytosis (mean leukocyte count, 10.5 x 109/L; range, 4.3 to 19.4 x 10 9 /L). Leukopenia (leukocyte count, < 3.5 x 109/L) was not observed. Anemia (hematocrit, < 0.35 [ 400 x 109/L) occurred in 65% of patients with active

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disease. The mean platelet count was 481 x 109/L (range, 113 to 1017 x 109/L). Thrombocytopenia (platelets, 113 x 109/L) was noted in only one patient before therapy. Response to treatment was associated with a parallel resolution of thrombocytosis in all cases. These findings are similar to our previous observations (5, 6). Before treatment, the erythrocyte sedimentation rate (ESR, Westergren method) correlated with disease activity in 80% of patients (mean, 71 mm/h; range, 17 to 140 mm/h). Serum immunoglobulin levels before treatment were generally within the normal range. The use of prednisone and daily cyclophosphamide therapy occasionally resulted in persistent hypogammaglobulinemia, which did not correlate with clinical response to therapy. Pathology The pathologic manifestations of Wegener granulomatosis in the upper and lower airway of our patients are summarized in Table 1 and have been reported in detail elsewhere (15-17). Eighty-two open lung biopsies were done. Combined vasculitis and necrosis were found in 89% of biopsy samples; granulomas and necrosis were found in 90%; and the combinations of granulomas and vasculitis as well as vasculitis, necrosis, and granulomatous inflammation were found in 91% of biopsy specimens (16) (Figure 6). Fifty-nine transbronchial biopsies were done in 48 patients. In only four specimens (7%) was vasculitis identified, and granuloma were present in three of those four. The small amount of tissue available in biopsy specimens from the head and neck may make it difficult or

impossible to identify pathologic features of Wegener granulomatosis. Both vasculitis and necrosis were found in 23% of upper-airway biopsy specimens; vasculitis and granulomatous inflammation were present in 21%; and in only 16% were vasculitis, necrosis, and granulomatous inflammation all present (15). Diagnostically useful tissue in the upper airway was obtained in decreasing order of frequency from the paranasal sinuses, nose, and the subglottic region (see Table 1). This order may reflect the quantity of tissue usually obtained by each procedure. The characteristic finding from renal biopsy in patients with Wegener granulomatosis was segmental necrotizing glomerulonephritis, which was usually focal (Figure 7, left) (18-20). One hundred and forty-four renal biopsies were done in 103 patients in our study. Varying degrees of segmental necrotizing glomerulonephritis were noted in 80%. Vasculitis unrelated to glomerular vessels occurred in 8% of specimens (Figure 7, right), and vasculitis and granulomatous changes were both present in 3% of specimens. In one patient, large necrotizing granulomas presented as a renal mass lesion. Skin specimens most commonly showed small vessel leukocytoclastic vasculitis and, less commonly, dermal necrotizing granulomas or necrotizing vasculitis involving larger dermal arteries or veins. Seventy-nine percent of patients had at least one biopsy specimen with evidence of vasculitis. Eighty-nine percent of patients had vasculitis, granulomatous changes, or both in these specimens. The remainder of patients in whom biopsy findings were less diagnostic had evidence of glomerulonephritis shown by renal biopsy.

Table 1. Pathologic Findings from Open-Lung and Upper-Airway Biopsy Samples in Patients with Wegener Granulomatosis* Variable Nasal (n = 60)

Paranasal Sinuses (n = 27)

Type of Inflammation Larynx (n = 17)

< Parenchymal changesf Geographic necrosis^ Poorly formed granulomas Scattered giant cells Microabscesses Microabscesses plus granulomas Vascular changes§ Granulomatous vasculitis Acute vasculitis Chronic vasculitis Fibrinoid necrosis Cicatricial changes II

n

Lung

(n = 82)

(m,\

n (,v)

12(20) 28(47) 28(47) 20(33) 12(20)

15(56) 16(59) 16(59) 10(37) 9(33)

3(18) 4(23) 4(23) 3(18) 3(18)

56(68) 48(59) 64(78) 53(65) 56(68)

4(7)

4(15)

0(0)

10(17) 14(23) 6(10) 0(0)

8(30) 8(30) 3(11) 1(4)

0(0) 1(6) 0(0) 1(6)

NG 8(22)1 NNG 21(26) 30 (37) 71(87) 9(11) 33(40)

NG 6(7)** NNG 8(10) 23 (28) 23 (28) 5(6) 13 (16)

* Data combined from references 25 and 26. NG = necrotizing granulomas; NNG = non-necrotizing granulomas. t Sarcoid-like granulomas were not seen in any biopsy samples from the upper airway and were found in only 3 (4%) from the lung. $ Geographic necrosis was defined as parenchymal necrosis characterized by a basophilic, granular center with a serpentine border often lined by a peripheral rim of palisading histocytes and multinucleated giant cells. § Capillaritis was observed in 31% of open-lung biopsy specimens and was characterized primarily by acute inflammation. II Cicatricial changes are nonspecific and should not be used as diagnostic criteria. 1 Data in this column (six entries) refer to the arteries. ** Data in this column (six entries) refer to the veins. 492

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Figure 6. Lung biopsy showing a necrotizing granuloma characteristic of Wegener granulomatosis. Left. An area of necrosis (seen at right) is surrounded by afibroinflammatoryinfiltrate that contains multinucleated giant cells. (Hematoxylin and eosin stain, 100 x original magnification). Right. Another site in this biopsy sample shows necrotizing vasculitis that involves a pulmonary arteriole. The destructive inflammatory infiltrate is eccentric, transmural, and has destroyed the inner and outer elastic laminae. (Verhoeff elastic stain, 200 x original magnification).

Clinical Outcome One hundred and thirty-three patients (84%) were treated with standard therapy (daily cyclophosphamide and glucocorticoids). Eight (5.0%) received only lowdose cyclophosphamide therapy. Ten patients (6.0%) were treated with only glucocorticoids, and 6 patients (4.0%) who never received cyclophosphamide were treated with other cytotoxic agents and glucocorticoids. Standard treatment resulted in marked improvement or partial remission in 91% of patients and complete remission in 75% of patients. Among those patients who achieved remission while receiving standard therapy, conversion from daily to alternate-day prednisone occurred within a median of 3.2 months. The median time to complete discontinuation of glucocorticoids was 12

months. Although some patients achieved complete remission within a few months, the median time for all patients receiving standard therapy to achieve remission was 12 months (Figure 8). Some patients (8.3%) with seemingly intractable disease eventually did achieve remission up to 4 to 6 years after initiation of therapy. Fifty percent of complete remissions were followed by one or more relapses. Relapses occurred from 3 months to 16 years after achieving remission. If outcome, as measured by remission, were expressed in terms of total patient years of follow-up (1229 patient years), 46% of all patients' time during the study was spent in remission. When remission analysis focused only on the 98 patients with at least 5 years of follow-up, several other important observations emerged. Remission was

Figure 7. Renal abnormalities in Wegener granulomatosis. Left. A segmental necrotizing glomerular lesion (Hematoxylin and eosin stain, x 250 original magnification). Right. Necrotizing vasculitis withfibrinoidnecrosis is present in the extraglomerular tissue of this renal biopsy specimen (Hematoxylin and eosin stain, x 250 original magnification). 15 March 1992 • Annals of Internal Medicine • Volume 116 • Number 6

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Figure 8. Graphic representation of the cumulative remission rate from the beginning of standard treatment. The cumulative rate is illustrated only for those patients (75% of total) in whom complete remission occurred. Although 50% of all individuals who achieved remission did so within 12 months, 20% required treatment for over 2 years before all features of disease had resolved. The remaining 8.3% of patients achieved remission after 48 months.

achieved at least once in 96% of patients. However, 49% later experienced at least one relapse. Forty-four percent of patients had remissions of more than 5 consecutive years duration. Thirteen percent of patients in this group experienced subsequent relapse. Similarly, 10 of 54 patients (18.5%) with over 10 years of follow-up experienced remissions of at least 10 consecutive years; two (20%) of these patients later relapsed. Ten patients (6.0%) were treated with only glucocorticoids during the course of our study. Six patients had limited (no evidence of renal disease) and four had generalized disease. Only two of six patients with limited Wegener granulomatosis achieved sustained remission. One of four patients with limited disease improved while receiving glucocorticoid therapy but did not achieve remission and later died of active Wegener granulomatosis. All four patients with generalized disease who received only glucocorticoid therapy died of active Wegener granulomatosis. Deaths among patients treated with only glucocorticoids occurred before rec-

ognition of the efficacy of cyclophosphamide therapy (5, 6). Eight patients (5.0%) were treated exclusively with low-dose daily cyclophosphamide. Four patients had limited disease, and four had generalized disease. Two of the four patients with glomerulonephritis had significant renal failure (serum creatinine, 389 /imol/L [4.4 mg/dL] and 592 /xmol/L [6.7 mg/dL], respectively) when cyclophosphamide treatment was initiated. Both patients died within 1.5 years due to active Wegener granulomatosis and end-stage renal disease. Two patients with glomerulonephritis had normal serum creatinine values at the start of cyclophosphamide therapy and achieved remission after about 2 years. These patients remained in remission without medication for 2 and 6 years, respectively, and were then lost to follow-up. All four patients with limited Wegener granulomatosis who were treated with only cyclophosphamide achieved remission after 1 to 2.5 years of therapy and have remained in remission without cyclophosphamide therapy for 1 to 11 years.

Morbidity

Figure 9. Subglottic (tracheal) stenosis. Magnetic resonance imaging (Picker, 0.5 Tesla magnet, Tl weighted image). Arrows show two foci of subglottic stenosis above the tracheostomy site. Failure of dilatations to restore normal tracheal patency led to tracheal reconstructive surgery that was only partially successful. 494

We divided morbidity into three categories: that which resulted from disease only, from disease plus treatment, and from treatment only. Permanent diseaserelated morbidity occurred in 86% of patients and included chronic renal insufficiency (42%), hearing loss (35%), cosmetic and functional nasal deformities (28%), tracheal stenosis (13%), and visual loss (8%). Many patients experienced more than one permanent type of morbidity. Renal insufficiency was often severe; the median creatinine level was 225.4 /miol/L (2.55 mg/dL). Although the most common histopathologic renal abnormality was focal segmental glomerulonephritis, most patients with irreversible renal impairment had developed varying degrees of diffuse proliferative, crescentic, necrotic, and sclerotic lesions. Of our 158 patients, 17 (11%) eventually required dialysis, and 5% (about half of the patients needing dialysis) had renal transplantation. All eight renal transplant

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recipients were in remission and were not receiving immunosuppressive medications at the time of surgical engraftment. Follow-up after transplantation varied from 6 months to 13 years (mean, 5 years). Only one patient experienced recurrence of active Wegener granulomatosis that contributed to renal failure. This observation has reinforced our belief in the feasibility of renal transplantation in patients with Wegener granulomatosis who are in remission. Hearing loss was related to recurrent serous or suppurative otitis media, sensorineural impairment, or to a combination of these factors. Most affected patients had partial unilateral or bilateral hearing loss (33%) that required hearing aids. Rarely, complete unilateral (1%) or bilateral (1%) deafness occurred. Five patients (3%) required mastoid sinus exenterations for secondary chronic infection or Wegener granulomatosis that was unresponsive to medical therapy. Nasal deformity occurred only rarely in patients without concurrent chronic sinus disease. The emotional impact of this deformity is usually substantial. Most affected patients were eager to have nasal cosmetic surgery. Concern about relapsing disease, however, led to restraint in carrying out such procedures. Of our 158 patients, 25 (16%) had tracheal stenosis (Figures 9 and 10). The most common symptom was shortness of breath. Symptoms and findings in five patients were modest and resolved during the course of treatment. In 20 patients, subglottic tracheal stenosis was irreversible. In 12 patients with severe tracheal stenosis the presentation included stridor and required emergency tracheostomy. Three patients had moderate degrees of stenosis that permitted manual or laser dilatation without a preceding tracheostomy. In four patients, mild fixed stenosis was followed but not treated during serial examinations. Five patients failed to achieve adequate subglottic patency after multiple attempts at dilatation and required open tracheal reconstruction procedures. Visual loss (8%) occurred primarily as the result of retro-orbital Wegener granulomatosis, taking the form of a pseudotumor or mass lesion (see Figure 5, bottom right). The histopathologic features of pseudotumors varied within and between specimens with regard to the

extent of inflammatory disease and fibrosis. Extensive fibrotic changes in chronic lesions may explain the relative resistance of this problem to treatment. Permanent morbidity attributed to disease plus medical or surgical treatment or both included chronic sinus dysfunction (47%) and pulmonary insufficiency (17%). The combined effects of disease activity, upper airway surgery to provide drainage of impacted sinuses or to obtain diagnostic material, and medical therapy probably all contributed to atrophic rhinitis and sinusitis, chronic mucosal crusting, impaired mucosal immunity, and recurrent infections. Staphylococcus aureus was the most common cause of purulent sinusitis and was treated using antibiotics and sinus irrigation. Persistent or recurrent infections also required surgical drainage. Clinical distinction between worsening sinus disease due to Wegener granulomatosis, infection, or both, was often difficult. In the absence of purulent drainage and a prompt response to antibiotics, surgical drainage and biopsy were often required for a more definitive diagnosis. Most patients, regardless of disease activity, had mucosal glandular atrophy. They required daily (one to three times per day) saline irrigations to minimize accumulation of sinus and nasal secretions and crusts associated with an increased risk for impaction and infection. Serial pulmonary function studies documented moderate to severe degrees of progressive pulmonary insufficiency in at least 17% of patients. We could not distinguish to what degree restrictive changes were caused by fibrosis that followed active Wegener granulomatosis, by cyclophosphamide-induced pneumonitis, or by a combination of these factors. Endobronchial lesions and scarring due to Wegener granulomatosis caused obstructive lung disease and recurrent postobstructive pneumonias in several patients. Some forms of morbidity were attributed solely to treatment toxicity, when complications were well known medication side effects and were not known to be manifestations of untreated Wegener granulomatosis. Transient, mild to moderate cyclophosphamide-induced hair loss occurred in 17% of patients, and glucocorticoid-induced diabetes mellitis occurred in 8%, of whom 3% required insulin. All glucocorticoid-treated patients

Figure 10. Tracheal stenosis in patients with Wegener granulomatosis. Sixteen percent of all patients had tracheal stenosis. In a minority, lesions were reversible with immunosuppressive therapy. However, most patients required surgical intervention to restore adequate ventilation. * Totals exceed 100% because some patients required more than one surgical intervention. ** Indicates mild stenosis. Open rec = tracheal reconstructive surgery; Trach = tracheostomy. 15 March 1992 • Annals of Internal Medicine • Volume 116 • Number 6 Downloaded From: http://annals.org/ by a University of Birmingham User on 07/25/2013

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experienced transient Cushingoid features. Examples of persistent or more permanent treatment-associated morbidity included cyclophosphamide-cystitis (43%), bladder cancer (2.8%), myelodysplasia (2%) and glucocorticoid-related cataracts (21%), fractures (11%), and aseptic necrosis (3%). In 28 women, ranging in age from 18 to 35 years, adequate information was available to estimate fertility status after at least 1 year of therapy with daily lowdose cyclophosphamide. Sixteen patients (57%) had stopped having menses for more than 1 year, were unable to become pregnant, or had hormonal studies that supported the impression of ovarian failure. Data regarding fertility and hormonal status in men were not available. To determine whether cyclophosphamide could be implicated in the genesis of malignancies, the malignancy rate among patients with Wegener granulomatosis (791 per 100 000 persons annually) was compared with that in the National Cancer Institute Registry (1982 to 1986) for adult men and women in the general population (335 per 100 000 persons annually). The results indicate a 2.4-fold overall increase in malignancies, a 33-fold increase in bladder cancers (ratio of cases observed to those expected, 4 to 0.12), and an 11-fold increase in lymphomas (ratio of cases observed to those expected, 2 to 0.18). The latency period from the start of cyclophosphamide therapy to detection of transitional cell carcinoma of the bladder varied from 7 months in one patient who was receiving daily cyclophosphamide, to 12 years in a patient who had not received cyclophosphamide for 10 years. Cyclophosphamide-treated patients who have experienced hematuria unrelated to glomerulonephritis have been evaluated using cystoscopy and bladder biopsy. All cyclophosphamide-treated patients, even after treatment has been stopped, have continued to have urinary cytologic examinations. All four patients (two men and two women) with bladder cancer developed hematuria (microscopic hematuria in three, gross hematuria in one) in the absence of red blood cell casts, which led to cystoscopic evaluation and a subsequent diagnosis of malignancy. One patient also had atypical cells observed during urinary cytologic screening before the diagnosis of bladder cancer. Features that might enhance the risk for cyclophosphamideinduced bladder cancer, such as obstructive uropathy and neurogenic bladder, were not present in any of these patients. Two patients developed lymphomas after 1.5 and 8.6 years of cyclophosphamide treatment, respectively. Myelodysplasia followed 1.6, 9.6, and 13 years of similar therapy in three patients, respectively.

quired hospitalization and intravenous antibiotics. Examples of serious infections included pneumonias (57 episodes, 39% of serious infections) due to Pseudomonas aerugenosa (8 episodes), Staphylococcus aureus (8 episodes), and fungal organisms such as Coccidioides immitis, Aspergillus fumigatus, and Candida albicans (8 episodes), Hemophilus influenza (7 episodes), Pneumocystis carinii (6 episodes), Streptococcus pneumonia (3 episodes), Mycobacterium tuberculosis (1 episode), Mycobacterium avium-intracellulare (1 episode); skin infections (38 episodes, 26% of serious infections) that were most often due to herpes zoster (34 episodes); and bacterial or fungal sepsis (13 episodes, 9% of serious infections). Although sinus infections of bacterial origin were common, most patients were treated by their personal referring physicians on an outpatient basis using oral antibiotics. The precise frequency of such therapy is unclear, but 9% of all serious hospital-treated infections involved the sinuses. When medical therapy, including sinus irrigation, superficial debridement, and antibiotics was unsuccessful, surgical sinus drainage was done. Fifty percent of all serious bacterial, Pneumocystis, and fungal infections (0.208 infections per patient year) occurred during periods of daily glucocorticoid therapy. A significantly smaller proportion of serious infections occurred during alternate-day therapy with glucocorticoids (21%), single agent cytotoxic therapy (16%), and periods without therapy (12%). This observation underscores the rationale behind the change from daily to alternate-day glucocorticoid therapy as quickly as was clinically feasible. The incidence of cutaneous herpes zoster was 0.004 infections per patient year during periods of no treatment and was about 10-fold increased in patients receiving daily or alternate-day glucocorticoids or only daily cyclophosphamide therapy. Compared with periods of no treatment, the frequency of herpes zoster infection was increased 20-fold when glucocorticoids and cyclophosphamide were used concurrently. Thus, glucocorticoids and cyclophosphamide independently and in combination enhanced the risk for herpes zoster infections. Mortality Twenty percent of all patients in our study died. In 13% of patients, death could be completely or partially attributed to active Wegener granulomatosis, chronic morbidity from previously active disease, complications of treatment, or a combination of these factors. Factors contributing to death included renal disease (3%), pulmonary disease (3%), concomitant renal and pulmonary disease (1%), infection (3%), and malignancy (2.5%). No significant differences in morbidity and mortality were noted between men and women.

Infectious Complications Because the degree to which tissue damage (such as that leading to impaired mucosal immunity) or immunosuppressive therapies led to infections was unclear, these complications are reported separately. Seventythree patients (46%) experienced 140 serious infections over 1229 patient years (0.11 infections per patient year). Serious infection was defined as that which re496

Discussion In 1973 Fauci and Wolff (5) reported the initial prospective NIH experience with Wegener granulomatosis. Our studies, which now extend over 24 years, have enhanced our understanding of the broad spectrum of organ system involvement, the atypical and indolent forms of disease, the efficacy of standard therapy to

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induce remission, and the tendency of patients to relapse and accrue additive morbidity from both disease and treatment. Our 158 patients (followed for up to 24 years) were remarkably similar to the 18 patients in our earlier study cohort with regard to the frequency and quality of clinical abnormalities. An important observation that has been repeatedly confirmed since the early reports by Klinger (1) and Wegener (2, 3) is that the airway is almost always initially involved in Wegener granulomatosis. Although upper or lower respiratory symptoms (or both) are usually present, about 34% of patients with radiographic, biopsy-proven, pulmonary abnormalities may be asymptomatic. We have recently shown that some persons with active Wegener granulomatosis, who lack airway symptoms and who have normal chest radiographs and computerized axial tomographic results, may have neutrophilic alveolitis and pulmonary production of ANCA as determined by bronchoalveolar lavage analysis (21, 22). Although it is not known whether similar findings occur in sinus lavage specimens, we have observed significant abnormalities of the nasal mucosa and sinus radiographs in asymptomatic patients. These findings have practical application in the evaluation of patients in whom Wegener granulomatosis is suspected. The upper airway and lungs of such patients should be studied by direct inspection or imaging techniques, even when these sites are not the source of symptoms. Our current experience has confirmed the life-saving potential of daily therapy with cyclophosphamide and glucocorticoids for this once usually fatal disease (7). However, long-term follow-up has also produced greater awareness of disease relapse in about half of our patients and serious morbidity resulting from the disease and its treatment. Our standard protocol was designed to minimize daily glucocorticoid therapy. In those patients experiencing partial or complete remission within 4 to 8 weeks of starting daily therapy with cyclophosphamide and glucocorticoids, prednisone was gradually tapered over the next 4 to 8 weeks to an alternate-day schedule. Among the 75% of patients who achieved remission, a median of 3.2 months was required to taper daily glucocorticoid therapy to an alternate-day schedule, and a median of 12 months was required to discontinue glucocorticoids entirely. Patients who did not achieve or sustain remission received longer courses of glucocorticoid therapy. Despite efforts to minimize the use of glucocorticoids, such therapy ultimately contributed to opportunistic infections, (especially during the period of daily glucocorticoid use), osteoporosis, fractures, cataracts, and Cushingoid features. The frequencies of cyclophosphamide-induced cystitis (43%), bladder cancer (2.8%), and myelodysplasia (2%) among our patients were higher than those previously recognized (6). The known extended latency period for expression of malignancy, even after discontinuation of treatment with alkylating agents, is of great concern. Treatment-related morbidity has led us to search for safer and effective alternative therapies. We have evaluated the potential efficacy of intermittent high-dose intravenous ("pulse") cyclophosphamide (23), trimethoprim-sulfamethoxazole, and low-dose weekly meth-

otrexate therapies. Our interest in pulse cyclophosphamide stemmed from its successful application in the treatment of systemic lupus erythematosus with nephritis (24-27). After 4 months of pulse cyclophosphamide therapy, 13 of 14 patients (93%) with Wegener granulomatosis markedly improved, and half had achieved remission. Despite further treatment over 6 to 24 months, however, 72% of patients were unable to sustain remission. Our patients received monthly high-dose intravenous cyclophosphamide and daily prednisone that was later tapered to alternate-day therapy after clinical improvement. Steppat and Gross (28) also used a monthly pulse cyclophosphamide protocol and reported results similar to ours. Their protocol differed in that monthly high-dose glucocorticoid therapy was given as well. Other, as yet untried, pulse cyclophosphamide regimens may prove more beneficial. Several reports have suggested that trimethoprim-sulfamethoxazole therapy may be useful in the treatment of Wegener granulomatosis (29-33). The anecdotal nature of these reports, the tenuous nature of the diagnosis in some cases, the use of concurrent immunosuppressive therapies, and failure to rule out infection for which trimethoprim-sulfamethoxazole may be an effective antimicrobial, all cast some doubt on purported efficacy (34). We studied this agent in an ongoing prospective open study. Patients were required to have active biopsy-proven disease, no evidence of infection, and to have not initiated or increased immunosuppressive therapies for at least 3 months. Thus far, only one of nine patients has had prolonged improvement while receiving trimethoprim-sulfamethoxazole therapy (one double-strength tablet, twice daily). This experience has reinforced our skepticism regarding the role of trimethoprim-sulfamethoxazole in the treatment of Wegener granulomatosis. The benefits of methotrexate in the treatment of rheumatoid arthritis (35-41) and rheumatoid vasculitis (42) led to initiation of a trial of low-dose weekly methotrexate (0.15 to 0.30 mg/kg) in patients with systemic vasculitides, including Wegener granulomatosis. Although remissions have occurred in 14 of 18 patients (unpublished observations), our impressions remain guarded because of the brief (1 year) follow-up period. Further study is necessary to determine what role methotrexate will play in the treatment of Wegener granulomatosis. Without a better understanding of the events that trigger and perpetuate expression of Wegener granulomatosis, nonspecific immunosuppressive therapies are not likely to provide uniform long-term remissions without relapse. The heterogeneity of our patient sample with regard to age, geographic origins, previous illness, environmental inhalant exposure (data not shown), and the inability to identify microorganisms in lung tissue or bronchoalveolar lavage fluid (21) casts doubt on whether Wegener granulomatosis is triggered by any single agent. Stimulation of the upper or lower airway by various airborne substances may, in a predisposed person, lead to systemic illnesses, such as Wegener granulomatosis. Whether proteinase-3 antibodies play a role in an airway-mediated systemic illness being expressed as Wegener granulomatosis is unclear (43-45). Our imperfect understanding of Wegener granuloma-

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tosis leaves us to apply broadly immunosuppressive therapies in the hope of producing remission and minimizing disease and treatment-associated morbidity. Standard therapy with daily cyclophosphamide and glucocorticoids is currently the best known means of achieving these ends. However, drug toxicity associated with such treatment is substantial and requires continued efforts to better understand disease pathophysiology and to identify effective alternative less toxic therapy. Acknowledgments: The authors thank the National Institute of Allergy and Infectious Diseases Clinical Fellows and Clinical Center nursing staff for the care of our patients and Mary Rust for preparation of the manuscript. Requests for Reprints: Gary S. Hoffman, MD, National Institutes of Health, Building 10, Room 11B12, Bethesda, MD 20892. Current Author Addresses: Drs. Hoffman, Kerr, Leavitt, Lebovics, Travis, Rottem, and Fauci and Ms. Hallahan: National Institutes of Health, 9000 Rockville Pike, Building 10, Room 11B12, Bethesda, MD 20892. References 1. Klinger H. Grenzformen der periarteritis nodosa. Frankf Z Pathol. 1931;42:455-80. 2. Wegener F. Uber generalisierte, septische efaberkrankungen. Verh Dtsch Pathol Ges. 1936;29:202-10. 3. Wegener F. Uber eine eigenartige rhinogene granulomatose mit besonderer beteiligung des arterien systems und der nieren. Beitr Pathol Anat Allg Pathol. 1939;36-68. 4. Pinching AJ, Lockwood CM, Pussell BA, Rees AJ, Sweny P, Evans DJ. Wegener's granulomatosis: observations on 18 patients with severe renal disease. Q J Med. 1983;208:435-60. 5. Fauci AS, Wolff SM. Wegener's granulomatosis: studies in eighteen patients and a review of the literature. Medicine. 1973;52:535-61. 6. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 1983;98:76-85. 7. Walton EW. Giant cell granuloma of the respiratory tract (Wegener's granulomatosis). Br Med J. 1958;2:265-70. 8. Hollander D, Manning RT. The use of alkylating agents in the treatment of Wegener's granulomatosis. Ann Intern Med. 1967;67: 393-8. 9. Reza MJ, Dornfeld L, Goldberg LS, Bluestone R, Pearson CM. Wegener's granulomatosis. Long-term followup of patients treated with cyclophosphamide. Arthritis Rheum. 1975;18:501-6. 10. Van Der Woude FJ, Lobatto S, Permin H, van der Giessen M, Rasmussen N, Wiik A. Autoantibodies against neutrophils and monocytes: Tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet. 1985;1:425-9. 11. Specks U, Wheatley CL, McDonald TJ, Rohrbach MS, DeRemee RA. Anticytoplasmic autoantibodies in the diagnosis and follow-up of Wegener's granulomatosis. Mayo Clin Proc. 1989;64:28-36. 12. Nolle B, Specks U, Liidemann J, Rohrback MS, DeRemee RA, Gross WL. Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener's granulomatosis. Ann Intern Med. 1989;111:28-40. 13. Liidemann J, Csernok E, Ulmer M, Lemke H, Utecht B, Rautmann A. Anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis: immunodiagnostic value, monoclonal antibodies and characterization of the target antigen. Neth J Med. 1990;36:157-62. 14. Cohen Tervaert JW, Huitem MG, Hene RJ, Sluiter WJ. Prevention of relapses in Wegener's granulomatosis by treatment based on anti-neutrophil cytoplasmic antibody titer. Lancet. 1990;336:709-11. 15. Devaney KO, Travis WD, Hoffman GS, Leavitt RY, Lebovics R, Fauci AS. Interpretation of head and neck biopsies in Wegener's granulomatosis. A pathologic study of 126 biopsies in 70 patients. Am J Surg Pathol. 1990;14:555-64. 16. Travis WD, Hoffman GS, Leavitt RY, Pass HI, Fauci AS. Surgical pathology of the lung in Wegener's granulomatosis. Review of 87 open lung biopsies from 67 patients. Am J Surg Pathol. 1991;15: 315-33. 17. Travis WD, Colby TV, Lombard C, Carpenter HA. A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Pathol. 1990;14:112-25. 18. Antonovych TT, Sabnis SG, Tuur SM, Sesterhenn IA, Balow J E . Morphologic differences between polyarteritis and Wegener's granulomatosis using light, electron and immunohistochemical techniques. Mod Pathol. 1989;2:349-59.

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19. Watanabe T, Yoshikawa Y, Toyoshima H. Morphological and clinical features of the kidney in Wegener's granulomatosis. A survey of 28 autopies in Japan. Jap J Nephrol. 1981;23:921-30. 20. Weiss MA, Crissman JD. Renal biopsy findings in Wegener's granulomatosis: Segmental necrotizing glomerulonephritis with glomerular thrombosis. Hum Pathol. 1984;15:943-56. 21. Hoffman GS, Sechler JM, Gallin JI, Shelhamer JH, Suffredini A, Ognibene FP, et al. Bronchoalveolar lavage analysis in Wegener's granulomatosis. Am Rev Respir Dis. 1991;143:401-7. 22. Baltaro RJ, Hoffman GS, Sechler JM, Suffredini AF, Shelhamer JH, Fauci AS, et al. Immunoglobulin G antineutrophil cytoplasmic antibodies are produced in the respiratory tract of patients with Wegener's granulomatosis. Am Rev Respir Dis. 1991;143:275-8. 23. Hoffman GS, Leavitt RY, Fleisher TA, Minor JR, Fauci AS. Treatment of Wegener's granulomatosis with intermittent high-dose intravenous cyclophosphamide. Am J Med. 1990;89:403-10. 24. Balow JE, Austin HA, Muenz LR, Joyce KM, Antonovych TT, Klippel JH, et al. Effect of treatment on the evolution of renal abnormalities in lupus nephritis. N Engl J Med. 1984;311:491-5. 25. Balow JE, Austin HA, Tsokos GC, Antonovych TT, Steinberg AD, Klippel JH. Lupus nephritis. Ann Intern Med. 1987;106:79-94. 26. Austin HA, Klippel JH, Balow JE, LeRiche NG, Steinberg AD, Plotz PH, et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med. 1986;314:614-9. 27. Sessoms SL, Kovarsky J. Monthly intravenous cyclophosphamide in the treatment of severe systemic lupus erythematosus. Clin Exp Rheumatol. 1984;2:247-51. 28. Steppat D, Gross WL. Stage adapted treatment of Wegener's granulomatosis. Klin Wochenschr. 1989;67:666-71. 29. De Remee RA, McDonald TJ, Weiland LH. Wegener's granulomatosis: observations on treatment with antimicrobial agents. Mayo Clin Proc. 1985;60:27-32. 30. West BC, Todd JR, King JW. Wegener's granulomatosis and trimethoprim-sulfamethoxazole: complete remission after a twentyyear course. Ann Intern Med. 1987;106:840-2. 31. Yuasa K, Tokitsu M, Goto H, Kato H, Shimada K. Wegener's granulomatosis: diagnosis by transbronchial lung biopsy, evaluation by gallium scintigraphy and treatment with sulfamethoxazole/trimethoprim. Am J Med. 1988;84:371-2. 32. De Remee RA. The treatment of Wegener's granulomatosis with trimethoprim/sulfamethoxazole: illusion or vision? Arthritis Rheum. 1988;31:1068-72. 33. Israel HL. Sulfamethoxazole-trimethoprim therapy for Wegener's granulomatosis. Arch Intern Med. 1988;148:2293-5. 34. Leavitt RY, Hoffman GS, Fauci AS. Response: the role of trimethoprim/sulfamethoxazole in the treatment of Wegener's granulomatosis. Arthritis Rheum. 1988;31:1073-4. 35. Anderson PA, West SG, O'Dell JR, Via CS, Claypool RG, Kotzin BL. Weekly pulse methotrexate in rheumatoid arthritis. Ann Intern Med. 1985;103:489-96. 36. Weinstein A, Marlowe S, Korn J, Farouhar F. Low dose methotrexate treatment of rheumatoid arthritis. Am J Med. 1985;79:331-7. 37. Kremer JM, Lee JK. The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis. Arthritis Rheum. 1986;29:822-31. 38. Williams HJ, Wilkens RF, Samuelson CO, Alarcon GS, Guttadauria M, et al. Comparison of low dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. Arthritis Rheum. 1985;28:721-30. 39. Hamdy H, McKendry RJ, Mierins E, Liver JA. Low dose methotrexate compared to azathioprine in the treatment of rheumatoid arthritis. Arthritis Rheum. 1987;30:361-8. 40. Tugwell P, Bennett K, Gent M. Methotrexate in rheumatoid arthritis. Indications, contraindications, efficacy and safety. Ann Intern Med. 1987;107:358-66. 41. Weinblatt ME, Kaplan H, Germain BF, Merriman RC, Solomon SD, Wall B, et al. Low dose methotrexate compared with auranofin in adult rheumatoid arthritis. A thirty-six week, double blind trial. Arthritis Rheum. 1990;33:330-8. 42. Espinoza LR, Espinoza CG, Vasey FB, Germain BF. Oral methotrexate for chronic rheumatoid arthritis ulcerations. J Am Acad Dermatol. 1986;15:508-12. 43. Falk RJ, Terrell RS, Charles LA, Jennette J C . Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci USA. 1990;87: 4115-9. 44. Van der Woude FJ, Van Es LA, Daha MR. The role of the C-ANCA antigen in the pathogenesis of Wegener's granulomatosis. A hypothesis based on both humoral and cellular mechanisms. Neth J Med. 1990;36:169-71. 45. Kallenberg CG. Antineutrophil cytoplasmic antibodies (ANCA) and vasculitis. Clin Rheumatol 9. (suppl) 1990;132-5.

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