CLINICAL REVIEW

Wegener's Granulomatosis: Prospective Clinical and Therapeutic Experience

With 85 Patients for 21 Years ANTHONY S. FAUCI, M.D.; BARTON F. HAYNES, M.D.; PAUL KATZ, M.D.; and SHELDON M. WOLFF, M.D.; Bethesda, Maryland

Eighty-five patients with Wegener's granulomatosis were studied for 21 years at the National Institutes of Health. Patients were treated with a protocol consisting of cyclophosphamide, 2 mg/kg body weight d, together with prednisone, 1 mg/kg body weight d, followed by conversion of the prednisone to an alternate-day regimen. Complete remissions were achieved in 79 of 85 patients (93%) . The mean duration of remission for living patients was 48.2 ( ± 3.6) months. Twenty-three patients are off all therapy for a mean duration of 35.3 ( ± 6.3) months without therapy. This study provides a prospective experience with Wegener's granulomatosis and shows that long-term remissions can be induced and maintained in an extremely high number of patients by the combination of daily cyclophosphamide and alternate-day prednisone therapy.

W E G E N E R ' S GRANULOMATOSIS is a distinct clinicopath-

ologic entity characterized by granulomatous vasculitis of the upper and lower respiratory tracts together with glo­merulonephritis. In addition, various degrees of dissemi­nated vasculitis involving both small arteries and veins may occur (1 , 2) . Although the cause is unknown, the disease is generally considered a hypersensitivity disorder because of the granulomata, inflammation of vessels, and glomerulonephritis, as well as circulating and apparently deposited immune complexes seen in some patients (3) . In previous reports, we have emphasized the clinical, dif­ferential diagnostic, pathologic, laboratory, immunologic, and therapeutic aspects of this disease (3-8). Before the institution of effective therapy, the prognosis for patients with this disease was extremely grave. Untreated, the dis­ease usually ran a rapidly fatal course, particularly after the recognition of functional renal impairment. The mean survival of untreated Wegener's granulomatosis was 5 months with 82% of patients dying within 1 year, and more than 90% of patients dying within 2 years (9) .

Although the use of corticosteroids was felt in earlier studies to improve the average time of survival to 12.5 months (10), the disease was usually fatal despite corti­costeroid therapy. The first report of the use of cytotoxic agents was in 1954 by Fahey and associates (1) who treated a 38-year-old man with nitrogen mustard and his condition improved. Since that time, there have been re­ports of treatment with various cytotoxic agents includ­ing alkylating agents, folic acid, and purine antagonists alone or in combination with corticosteroids (3) . In

some of these patients, clinical responses were favorable and there were significant long-term remissions.

In 1973, we first reported our prospective experience at the National Institutes of Health ( N I H ) with the use of cyclophosphamide, 1 to 2 mg/kg body weight • d, for patients with Wegener's granulomatosis (3) . Over a 12-year period, we had studied 18 patients, 15 of whom had an adequate trial of cytotoxic therapy. Of these 15 pa­tients, only 2 died of their disease, and 1 died of unrelated causes. The other 12 patients were reported to be in re­mission for up to 63 months after initiation of therapy. Of these 12 patients, 6 were off all drugs and were well from 2 to 24 months after cessation of therapy, at the time of the report. After that initial prospective study, other studies confirmed the dramatic therapeutic efficacy of cy­totoxic agents, particularly cyclophosphamide (11-15). A few studies reported favorable results with other cyto­toxic agents, but both anecdotal and reported experience showed that cyclophosphamide was the cytotoxic drug of choice in Wegener's granulomatosis (4, 7) .

Because the use of cytotoxic agents in non-neoplastic diseases is still a matter of concern with regard to short -and long-term side effects, it is important to evaluate and clearly show both the efficacy of the therapeutic regimen over long-term follow-up as well as the occurrence of toxic side effects seen over a prolonged period. We report our prospective experience in treating and closely study­ing 85 patients with well-documented Wegener's granulo­matosis over a 21-year period who were treated with chronic low-dose cyclophosphamide together with alter­nate-day corticosteroids.

Patient Population

Characteristics of the patient population are given in Table 1. The figures are similar to the mean age of 43.6 years and the male-to-female ratio of 1.6 to 1 that we originally reported for the first 18 patients in 1973 (3) . Eighty-two patients were white; 2, black; and 1, Hispan­ic. All patient-related information was gathered at NIH, and because every patient was followed there throughout the study the follow-up data were collected firsthand. For the initial admission, patients were kept hospitalized until they were at least in partial remission. Frequency of fol­low-up was every 2 to 3 months for patients in partial remission and every 4 to 6 months for patients in com­plete remission. After a patient had been in complete re­mission and off all therapy for 1 full year, follow-up visits

©1983 American College of Physicians

• From the Laboratory of Immunoregulat ion, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda. Maryland.

y g Annals of Internal Medicine. 1983;98:76-85.

were extended to one per year except if signs or symp­toms of disease reappeared, at which point the patient was admitted immediately to NIH.

Clinical Presentation

The presenting signs and symptoms in the patient groups are shown in Table 2. Initial clinical presentations span a broad range of manifestations. However, most pa­tients initially presented to their physicians with upper airway illnesses. These illnesses were usually related to severe and persistent rhinorrhea that did not respond completely to standard symptomatic treatment or pro­gressively worsened. This worsening was usually associ­ated with sinus drainage and pain in which upper airway mucosal ulcerations may or may not have been present. Otitis media usually related to blockage of the eustachian tube was seen in 2 5 % of patients at presentation. Pulmo­nary infiltrates shown on chest roentgenograms in 7 1 % of patients at the time of the presentation led to diagno­sis. However, less than half of these patients had signifi­cant symptoms that would have indicated serious lung disease, thus leaving a substantial proportion of patients with essentially asymptomatic pulmonary infiltrates. It was unusual for patients to present initially with func­tional renal impairment ( 1 1 % of patients); nonrenal manifestations almost invariably preceded functional re­nal disease. The risk of ultimate progression to end-stage renal disease in Wegener's granulomatosis was approxi­mately 30% in those patients with glomerulonephritis and azotemia before starting immunosuppressive therapy (16).

Organ System Involvement

The predominant organ system involvement in Wegen­er's granumolatosis is shown in order of frequency in Table 3. All patients had either upper airway and lung involvement, and most had both. Only 5 of 85 patients had no evidence of upper airway involvement of any sort, namely, no evidence of sinusitis, nasal involvement, or otitis media. Seventy-two patients (85%) had well-docu­mented renal disease, thus putting them into the category of generalized Wegener's granulomatosis (3, 4) .

LUNG DISEASE

Eighty of 85 patients (94%) had lung disease. This was shown by open thoracotomy and biopsy results in 57 patients, with the remaining 23 patients having pulmo­nary infiltrates shown on chest roentgenograms in the setting of well-documented disease in other organ sys-

Table 1 . Patients with Wegener's Granulomatosis, National Insti­tutes of Health Study

Patients, n 85 Men 48 Women 37

Mean age (range), yrs 40.6 ± 1.8 (14-75) Mean duration from time of

onset of symptoms to diag­nosis of Wegener's granulo­matosis (range) 8.3 ± 1.5 mos (2 wks-10 yrs)

Table 2. Presenting Signs and Symptoms in Wegener's Granulo­matosis

Sign or Symptom* Pati

n

ents

% Pulmonary infiltrates 60 71 Sinusitis 57 67 Joint (arthralgia or arthritis) 37 44 Fever 29 34 Otitis 21 25 Cough 29 34 Rhinitis or nasal symptoms 19 22 Hemoptysis 15 18 Ocular inflammation (conjunctivitis,

uveitis, episcleritis, and scleritis) 14 16 Weight loss 14 16 Skin rash 11 13 Epistaxis 9 11 Renal failure 9 11 Chest discomfort 7 8 Anorexia or malaise 7 8 Proptosis 6 7 Shortness of breath or dyspnea 6 7 Oral ulcers 5 6 Hearing loss 5 6 Pleuritis or effusion 5 6 Headache 5 6

* Miscellaneous: hoarseness or stridor, saddle nose, mastoiditis, 3 patients each; cranial nerve dysfunction, 3; parotid mass or pain, 2 each; nasolacrimal duct obstruction, thyroiditis, liver function test abnormality, blindness, peripheral neu­ropathy, ear pinna mass, pedal edema, adenopathy, anosmia, pericarditis, asthma, diabetes insipidus, Raynaud 's phenomenon, 1 patient each.

terns. Twelve of the 80 patients with lung disease had endobronchial involvement during the course of their dis­ease with 6 of the 12 patients having variable degrees of subglottal stenosis. Endobronchial biopsy rarely, if ever, established the initial diagnosis because of the usual non-specificity of the findings by this approach. However, en­dobronchial biopsy usually confirmed the presence of ac­tive disease in patients whose diagnosis already had been established and in whom endobronchial involvement rep­resented smoldering disease activity or relapse.

Lung biopsy results were similar to those previously reported (3, 4) with granulomata and vasculitis almost invariably being shown. On a rare occasion, lung biopsy showed granulomata without clearcut vasculitis, or vas­culitis without clearcut granulomata. However, the diag­nosis was always established by compatible diagnostic findings in other organ systems.

As previously reported (3, 4) , the characteristic and typical lung findings were multiple, bilateral nodal infil­trates that tended to cavitate. Pleural effusions were seen in approximately 20% of patients, hilar adenopathy was not seen, and pulmonary calcifications were extremely rare (3, 4, 17). We carefully examined pulmonary func­tion in 22 patients (18) and reported that obstruction to airflow was the commonest abnormality, found in 5 5 % of patients. Reduced lung volumes and diffusing capacity also occurred frequently, with 4 1 % of patients having reduced vital capacity, 36% having reduced lung capaci­ty, and 32% having increased residual volume and total lung capacity.

Small areas of atelectatic lung were frequently seen ad­jacent to parenchymal infiltrates during active pulmonary

Fauci et al. • Wegener's Granulomatosis 77

Table 3. Organ System Involvement in Wegener's Granulomato­sis

Organ System Pati

n

ents

Lung 80 94 Paranasal sinuses 77 91 Kidney 72 85 Joints 57 67 Nose or nasopharynx 54 64 Ear 52 61 Eye 49 58 Skin 38 45 Nervous system 19 22 Heart 10 12

disease. However, 7 of the 12 patients with documented endobronchial disease had variable degrees of atelectasis related to scarred endobronchial tissue or smoldering en­dobronchial disease in the face of relatively quiescent dis­ease in other organ systems. The atelectasis usually re­sponded to chest physical therapy; two patients needed repeated bronchoscopic examinations with dilatations, and one patient needed bronchoplasty with removal of the stenotic bronchial segment.

RENAL DISEASE

Seventy-two patients (85%) had well-documented re­nal disease. Results of percutaneous renal biopsy in 58 of these 72 patients showed renal disease, whereas the re­maining 14 patients had urinary sediment or functional abnormalities. We have previously reported the scope of renal disease in Wegener's granulomatosis (3, 4, 19). These findings were confirmed and remained consistent in the present larger group of patients.

The histopathologic findings shown in the renal biopsy specimens spanned a broad scope from mild focal and segmental glomerulonephritis with minimal urinary find­ings and little, if any, renal functional impairment, to fulminant diffuse necrotizing glomerulonephritis with proliferative and crescentic changes. It should be pointed out that granulomata and true arteritis were found ex­tremely rarely by renal biopsy. Extrarenal manifestations almost invariably precede renal disease in Wegener's granulomatosis. However, renal disease, once present, may progress from mild to severe glomerulonephritis within weeks and even days of its inception.

UPPER AIRWAY DISEASE

As mentioned, only 5 of 85 patients did not have any form of upper airway disease. The degree of involvement differed, ranging from rhinorrhea and nasal discomfort to nasal mucosal ulceration to sinusitis that could be mild or involve the bony walls of the sinuses. Otitis media usually resulting from blockage of the eustachian tube was seen in 2 5 % of patients. Other types of involvement related to the ear included suppurative otitis, cholesteatoma, and temporal bone granulomata. Five patients initially pre­sented with hearing loss, and at least 12 patients had a significant degree of hearing impairment during the course of the disease.

As previously reported, the histopathologic findings in the upper airways also differed (3) . Although granulo­matous vasculitis is the hallmark of the histopathology of Wegener's granulomatosis, this pattern was not invari­ably shown in biopsy specimens of the upper airway. Fif­ty percent of upper airway biopy specimens in our pa­tients (58 biopsies of the sinuses or nasopharynx were done) showed nonspecific changes of acute and chronic inflammation with necrosis. The remainder of the upper airway biopsy specimens usually showed either granulo­mata or vasculitis; very rarely did they show both. The likely reason for this is that large amounts of tissue are rarely available for examination from this area. Biopsy specimens of oral ulcerations from five patients showed acute and chronic inflammation. Twenty-four patients developed some degree of saddle nose deformity usually due to collapse of the nasal septal support of the bridge of the nose.

There are certain important points about the upper air­way disease of Wegener's granulomatosis that should be mentioned. The first point relates to the degree of upper airway destruction and the differential diagnosis of other upper airway destructive diseases such as idiopathic mid­line granuloma, and the upper airway midline destructive diseases associated with neoplasms such as midline ma­lignant reticulosis (3, 6, 20-23). These latter diseases fre­quently destroy and erode through the tissues, and even skin, of the face. In addition, the diseases frequently erode through the hard palate. Although severe upper airway disease in Wegener's granulomatosis can cause erosion through the walls of the sinuses, none of our pa­tients had erosion through the skin of the face or nose, and most importantly, no patient had perforation of the palate. Either of these findings should strongly indicate another localized midline destructive disease such as midline granuloma or a midline neoplasm.

Virtually every patient in the present study with seri­ous sinus or nasal disease developed secondary infection of these tissues, almost surely due to the damage of mu­cosal surfaces by the underlying disease and the subse­quent impairment of the ability to clear bacteria ade­quately. Staphylococcus aureus was the predominant organism cultured from the nose or sinus of every patient who developed an infection. The infection invariably re­sponded to anti-staphylococcal antibiotics, but irrigation with saline or drainage procedures such as maxillary an­tral windows or Caldwell-Luc operations were frequently done because of persistent or recurrent infection. Of note is the fact that even after the systemic disease was in complete remission after appropriate therapy, approxi­mately 80% of patients who had had severe disease at the outset also had upper airway symptoms. Not infrequent­ly, patients who had had a complete remission on therapy were felt to have had a relapse because of increased sinus symptoms together with an elevation of the erythrocyte sedimentation rate. However, on evaluation it was usual­ly found that the symptoms and the erythrocyte sedimen­tation rate elevation were related to smoldering upper airway infection, and both responded promptly to antibi­otics with or without drainage procedures. This latter

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observation cannot be overemphasized because increasing or reinstituting immunosuppressive therapy under these circumstances would obviously be contraindicated.

JOINT DISEASE

Sixty-seven percent of patients had some form of joint involvement during the course of the disease. Of these 57 patients with joint involvement, 33 had arthralgias with­out frank arthritis, whereas 24 had arthritis. The arthral­gias were generally polyarticular, symmetrically involv­ing small and large joints. When arthritis occurred, it was seen in the large joints, particularly the knees and ankles, and was never deforming. Joint fluid was rarely available for examination and was usually non-specific. The joint involvement generally paralleled disease activity in other organ systems. However, four patients had persistent ar­thralgias that were successfully treated with nonsteroidal anti-inflammatory agents despite complete remission in other organ systems, and the fact that the patients were no longer receiving immunosuppressive therapy.

EYE DISEASE

Eye involvement was seen in 49 patients ( 5 8 % ) . As we had previously reported (24) , involvement was multifac-eted and heterogenous among patients and included con­junctivitis, episcleritis, uveitis, optic nerve vasculitis, reti­nal artery occlusion, nasolacrimal duct obstruction, and proptosis. Fifteen of the 49 patients with eye involvement had proptosis resulting from retro-orbital mass lesions. Biopsy specimens from seven of these patients showed acute and chronic inflammation with or without granulo­matous vasculitis. The proptosis was noteworthy in that it was generally slow to respond to therapy of the under­lying disease. In fact, the proptosis was refractory to ther­apy in three patients despite the fact that lung, kidney, and other organ system disease was in complete remis­sion with cyclophosphamide and prednisone.

SKIN OR MUSCLE DISEASE

The incidence of skin disease in our 85 patients was 4 5 % , which is what we had reported in 1973 with our original 18 patients and is quite similar to that reported previously (3, 4 ) . The lesions can take several forms in­cluding papules, vesicles, palpable purpura, ulcers, and subcutaneous nodules (3 ) . The histopathologic findings range from nonspecific acute and chronic inflammation to characteristic necrotizing granulomatous vasculitis. The skin disease rarely dominates the clinical picture, is usually a minor part of the multisystem involvement, generally responds promptly to therapy, and parallels disease activity in other organ systems.

Four patients had symptomatic myopathy that could not be attributed to corticosteroid therapy. Biopsy speci­mens showed nonspecific inflammation with small vessel arteritis in two specimens.

NERVOUS SYSTEM DISEASE

Although early reports of Wegener's granulomatosis before the use of adequate therapy indicated that up to 50% of patients developed nervous system involvement

(25), the percentage is much lower in current experience. The percentage of patients with nervous system involve­ment in the present study was 22% (19 of 85 patients). Of these 19 patients, 9 had peripheral nervous system involvement with mononeuritis multiplex being the pre­dominant manifestation. Ten patients had central ner­vous system involvement. Of these, eight patients had cranial nerve abnormalities with cranial nerves II, V, VII, VIII, IX, and XII being involved in one, two, six, one, one, and one patient respectively. One patient had unexplained episodes of syncope, and another patient previously reported (26) had diabetes insipidus as part of his presentation that resolved as his disease was put into remission with therapy.

HEART DISEASE

Heart involvement was seen in ten patients. Six pa­tients had acute pericarditis, and two patients had cardi­tis. An additional two patients had the unusual finding of dilated congestive cardiomyopathy without previous clin­ical evidence of acute carditis. Both patients were women and both were resuscitated from cardiac arrests due to ventricular arrhythmias. It is unlikely that these patients had both Wegener's granulomatosis and idiopathic car­diomyopathy. They may have had subclinical carditis, recognized as it became manifested as a cardiomyopathy. Alternatively, because both patients developed this com­plication while receiving cyclophosphamide for their underlying disease, it is conceivable that the cardiomyo­pathy is directly related to this therapy. However, cardiomy­opathy as a result of chronic low-dose cyclophospha­mide has not been reported.

MISCELLANEOUS ORGAN SYSTEM INVOLVEMENT

In addition to the more classic organ system involve­ments mentioned above, individual patients had unusual findings that included granulomata in the parotid gland in one patient; granulomata in the mastoid bone in one patient; a posterior laryngeal mass that regressed on im­munosuppressive therapy in one patient; acute thyroiditis in one patient; necrotizing granulomata in the cervical vertebrae in one patient; unexplained ascites in one pa­tient; unexplained liver function abnormalities in five pa­tients, three of whom had percutaneous liver biopsy that showed nonspecific inflammation (triaditis) without granuloma or vasculitis; a granulomatous vocal cord mass in one patient; and a granulomatous nodule on the tympanic membrane in one patient.

Laboratory Data

As we have previously reported, there are no diagnos­tic laboratory findings in Wegener's granulomatosis; however, certain characteristic, although nonspecific, lab­oratory abnormalities have been seen (3) . Leukocyte counts were available for 64 of 85 patients before the institution of any form of therapy. The mean leukocyte count was 9560/mm 3 ( ± 548). No leukocyte count was less than 4000/mm 3 before therapy. This latter point should be emphasized because leukopenia is clearly not a feature of Wegener's granulomatosis. However, as we

Faucietal. • Wegener's Granulomatosis 7 9

have reported (6, 27), leukopenia can be seen in patients with lymphomatoid granulomatosis. This disease with lymphoproliferative features often evolves into a frank lymphoma and is often confused with Wegener's granulo­matosis (27). Anemia was seen in more than 50% of Wegener's granulomatosis patients before therapy. The anemia was generally normochromic and normocytic, and felt to be the anemia of chronic disease. In addition, thrombocytosis (platelet count greater than 400 000/ mm 3 ) was seen in approximately one third of patients. No patient had thrombocytopenia before therapy.

The erythrocyte sedimentation rate was elevated in ev­ery patient before therapy. Indeed, marked elevations were invariably seen during periods of disease activity with a mean level of 93 ( ± 3.1) m m / h (Westergren method) . Rheumatoid factor (latex fixation) was mea­sured in 44 patients before institution of therapy or dur­ing periods of disease activity and was positive in 27 pa­tients. The mean titer was 1:128 and was never greater than 1:4096. Thirty-two patients had determinations of serum immunoglobulin (Ig) levels before therapy, and elevations (usually of IgA and IgM) were seen in seven patients. Elevations of IgE levels were rarely seen. Deter­minations of circulating immune complexes by C l q bind­ing or Raji cell assays were done on 36 patients during periods of disease activity and were positive in 16 pa­tients. Tests for antinuclear antibody and lupus erythe­matosus cell preparations were done in every patient, and none were positive. No patients had circulating hepatitis B surface antigen. As we had previously reported, pa­tients were generally not anergic before therapy as ascer­tained by skin tests for delayed cutaneous hypersensitivi­ty (3, 28, 29).

Treatment Protocol

The protocol treatment regimen used in the present study consisted of initiating therapy with cyclophos­phamide, 2 mg/kg body weight • d orally, continued for variable periods. In addition to and simultaneously with the cyclophosphamide, patients also received prednisone, 1 mg/kg body weight • d orally. The daily prednisone was continued for approximately 2 to 4 weeks until the immunosuppressive effects of cyclophosphamide could be realized. The prednisone regimen was then gradually (over 1 to 2 months) converted to an alternate-day regi­men (60 mg on alternate days). After conversion to an alternate-day regimen, the dose was gradually tapered until the patient was no longer receiving prednisone and was maintained solely on cyclophosphamide. The dura­tion of time that patients received alternate-day predni­sone varied depending on the individual response to ther­apy. Most patients' regimens were tapered down to 20 mg or less of prednisone on alternate days over 6 months to 1 year. However, several patients received alternate-day prednisone for longer periods due to signs and symp­toms of inflammation that appeared as the dose was ta­pered. Cyclophosphamide was continued for at least 1 full year after a patient was clinically in complete remis­sion. After this period, which varied among patients, a tapering schedule was begun in which the dose of cyclo­

phosphamide was lowered by 25-mg decrements every 2 to 3 months. The drug was either discontinued or a dos­age was reached below which the patient was shown to have a flare of disease activity.

The prevailing philosophy of cyclophosphamide thera­py was to carefully monitor the peripheral leukocyte count and adjust and modify the cyclophosphamide dos­age accordingly. We aimed at never allowing the leuko­cyte count to drop below 3000 to 3500/mm3 which usual­ly resulted in a total neutrophil count of greater than 1000 to 1500/mm3 . Observation of the slope of decrease of the leukocyte count was essential to the proper adjust­ment of dosage. Because the effect of a given dose of cyclophosphamide on the leukocyte count was generally seen days after it was administered (5) , as the leukocyte count approached the neutropenia level adjustments needed to be made. If significant neutropenia occurred before adjusting the dose, serious neutropenia invariably occurred even after the drug was held for several days. In the early induction of therapy, we generally followed the leukocyte count at least every other day, and after the leukocyte count stabilized, we followed the counts at no greater intervals than every 1 to 2 weeks.

In patients who could tolerate only very low doses of cyclophosphamide because of neutropenia, and in whom greater doses of cyclophosphamide were needed because of persistent disease activity, we found that the addition of or increase in the dose of alternate-day prednisone al­lowed us to administer higher doses of cyclophosphamide with a lesser degree of leukopenia (7) . It is felt that the mechanism of this marrow-sparing effect of corticoster­oid in patients treated with cyclophosphamide is similar to that recently described in the mouse model, in which corticosteroids had a beneficial effect on marrow regener­ation after cyclophosphamide treatment, due most likely to an altering of cell cycle characteristics of granulocyte progenitor cells (30).

In a few patients with fulminant and rapidly progres­sive disease, we began cyclophosphamide therapy at 4 to 5 mg/kg body weight • d, using the leukocyte count to guide subsequent dosage adjustments. Under these cir­cumstances, prednisone (or a soluble parenteral equiva­lent) was usually given for the first few days at a dose of 2 mg/kg body weight • d followed by return to the corti­costeroid regimen described above.

Patients were either begun on the above treatment regi­men after admission to NIH, or, more commonly, the regimen was started by the referring physician in consul­tation with us before and while preparing for transfer of the patient to NIH. The regimen was begun because of the concern of irreversible organ system dysfunction, es­pecially renal failure, that might occur in the time it took to arrange transfer of the patient. Certain patients were started on azathioprine by their referring physicians, usu­ally in a dose of 2 mg/kg body weight • d. Most of these patients were switched to cyclophosphamide upon enter­ing the study.

C R I T E R I A FOR REMISSION

Because adjustments of the therapeutic regimen de-

g O January 1983 • Annals of Internal Medicine • Volume 98 • Number 1

pended for the most part on the clinical judgment con­cerning the state of disease activity and because there is no single laboratory determination or combination of lab­oratory tests that absolutely measured the state of disease activity, certain criteria for partial and complete remis­sion were established. These criteria were based on previ­ous extensive experience with the course of disease be­fore, during, and after treatment (3-5).

Partial remission was denned as clearcut suppression of the progression of disease activity with stabilization of renal abnormalities, both functional and urinary findings. In addition, pulmonary infiltrates should no longer prog­ress and should begin to resolve. Further, there should be no worsening of other organ system disease activity, and there should be a progression towards improvement. At this point, the erythrocyte sedimentation rate may still be considerably elevated, but nonetheless, it must be de­creasing progressively.

Complete remission is defined as the complete absence of evidence of active disease. Pulmonary infiltrates must clear completely or show evidence of stable scarring without signs of active inflammation. Renal function must stabilize or improve with no further evidence of active renal sediment. With regard to the latter point, proteinuria may persist for months or years in the pres­ence of completely inactive renal disease. In addition, mi­nor abnormalities of urine sediment may be seen that are compatible with previous glomerular damage without ev­idence of persistent activity as is seen with the presence of erythrocyte casts. Further, there should be no evidence of systemic inflammatory disease such as serositis and fever. Finally, the erythrocyte sedimentation rate must return to normal, or if it remains slightly abnormal, it must be explained by inflammation not directly related to the un­derlying disease activity. Specifically, this inflammation refers to recurrent and smoldering sinus infections that result from compromise of the previously damaged mu­cosal membranes and respond promptly to antibiotic therapy or irrigation and drainage.

Results of Therapy and Follow-up

INDUCTION OF REMISSION

The results of therapy in Wegener's granulomatosis are shown in Table 4. Of the 85 patients studied, complete remissions were induced and maintained in 79 patients for a remission-induction rate of 9 3 % . These 85 patients were followed at NIH for a mean of 51 ( ± 4 . 3 ) months. Seventy-five patients are still alive. Of the ten patients who died, six died with active disease, and four died in complete remission of causes either unrelated to their dis­ease or related to complications of long-term renal failure on dialysis.

Of the 75 patients alive and in remission, the mean duration of remission is 48.1 ( ± 3.6) months with a range of 7 months to 13.2 years. Twenty-three patients are no longer receiving therapy, and the mean duration of time without therapy is 35.3 ( ± 6.3) months. Fifty-two patients are still receiving therapy; the mean duration of therapy in the entire group of 85 patients who received therapy at one time is 46.6 ( ± 3.7) months. Virtually all

Table 4. Results of Therapy in Wegener's Granulomatosis

Patients with induction of complete remission, n/total (%) 79/85 (93)

Treatment failures (death due to ac­tive disease), n/total (%) 6/85 (7)

Mean duration of remission in living patients (range) 48.2 + 3.6 mos

(7 mos-13.2 yrs) Patients off all therapy, n 23 Mean duration of time off all therapy 35.3 i t 6.3 mos

patients still receiving therapy are in complete remission and are either being maintained on therapy for the mini­mal period of 1 year after induction of remission or are at some point in the gradual tapering schedule after the 1-year minimal period of induction of remission. Of the 52 patients still receiving therapy, 32 patients are receiving cyclophosphamide and prednisone, 9 are receiving cyclo­phosphamide alone, 6 are receiving prednisone alone, and 5 are receiving azathioprine and prednisone.

RELAPSES AND SMOLDERING DISEASE ACTIVITY

Of note is the fact that 25 patients who had achieved remission had some degree of relapse after it had been judged that the patient was in complete remission. Re­lapse usually occurred in patients in the process of having their cyclophosphamide treatment tapered. One of these patients ultimately died. The 24 remaining patients were promptly reinduced into remission by increasing the dose of cyclophosphamide and prednisone. Seven of these 24 patients are now in remission off all therapy. Only three patients had relapses after their cyclophosphamide and prednisone had been discontinued because of complete remission; all three patients were promptly put back into remission by reinstituting therapy.

Because patients were followed closely in the protocol, relapses were generally noted early and did not result in significant organ system dysfunction such as renal failure. Relapses were associated with premonitory findings such as marked elevation of erythrocyte sedimentation rate, arthralgias, skin lesions, and malaise. Because patients were carefully instructed to return for emergency admis­sion under these circumstances, serious complications such as renal failure were usually avoided. Furthermore, because 22 of the 25 patients who had relapse were re­ceiving therapy (albeit in a tapering schedule) at the time of the relapse, the full consequences were likely blunted.

CYCLOPHOSPHAMIDE VERSUS AZATHIOPRINE

In the present study, 23 patients received azathioprine at some time during the course of their disease. Eleven patients had been started on azathioprine therapy by their referring physicians because of concern by the pa­tient or physician over the potential toxic side effects of cyclophosphamide. Ten of 11 patients did not achieve satisfactory remission on the azathioprine regimen and had progressive organ system dysfunction, usually in the form of deteriorating renal function. All ten patients had the azathioprine discontinued and cyclophosphamide started. Unfortunately, several of these patients had al­ready developed irreversible organ system dysfunction on

Fauci et al. • Wegener's Granulomatosis 81

Table 5. Renal Transplantation in Wegener's Granulomatosis

Patient Donor Outcome

Age* Sex

yrs 48 M Cadaver Normal renal function for 5 years;

ultimately died of cryptococcal meningitis secondary to immu­nosuppressive therapy

29 M Father Normal renal function 8 years af­ter transplant; relapsed with transplanted kidney while re­ceiving azathioprine; switched to cyclophosphamide with rein-duction of remission

37 M Cadaver Normal renal function 4 years af­ter transplant; cyclophospham­ide being used for rejection pro­phylaxis

21 F Sister Normal renal function 16 months after transplant

* At time of transplant.

azathioprine. Each of these patients was felt to have had an adequate trial of azathioprine therapy in that the drug was administered for at least 4 to 6 weeks in every patient and for as long as several months in some patients. Every one of these patients achieved complete remission on cy­clophosphamide. The single patient who achieved remis­sion on azathioprine had also received prednisone and methotrexate together with azathioprine.

Nine patients had originally been started on cyclophos­phamide and had achieved a complete remission. Howev­er, during the extended period of cyclophosphamide ther­apy, these patients developed cyclophosphamide-induced cystitis. Azathioprine was substituted for cyclophos­phamide in each of these patients. Remission was main­tained in all but one patient, who had a serious renal and pulmonary relapse after being switched to azathioprine. The azathioprine was discontinued in this patient, and she was again given cyclophosphamide. On the latter reg­imen, the patient promptly achieved remission and is cur­rently only receiving alternate-day prednisone after an uneventful tapering of cyclophosphamide.

Another circumstance in which azathioprine was used was in prophylaxis of renal transplant rejection. Three patients who had achieved complete remission on cyclo­phosphamide and prednisone ultimately had all immuno­suppressive therapy discontinued, but had the residua of end-stage renal failure due to rapidly progressive glomer­ulonephritis early in the course of the disease, which had not been promptly treated until significant renal function impairment had occurred. These patients had renal trans­plants and then received the standard regimen of aza­thioprine and prednisone. One of these patients, previous­ly reported, had a relapse of Wegener's granulomatosis 4 years after azathioprine was begun (31). The patient was switched back to cyclophosphamide with prompt induc­tion of remission. This patient has remained on cyclo­phosphamide for the past 4 years as treatment for Weg­ener's granulomatosis as well as immunosuppression for rejection prophylaxis.

Although controlled studies carefully comparing the

efficacy of cyclophosphamide and azathioprine in the treatment of Wegener's granulomatosis have not been done, the present study strongly suggests that azathio­prine is not as effective as cyclophosphamide in the induction of remission in Wegener's granulomatosis. Azathioprine may be effective in certain patients in main­taining remission induced with cyclophosphamide when the cyclophosphamide is prematurely discontinued for reasons of toxicity, such as in patients who develop severe cystitis.

END-STAGE RENAL FAILURE AND RENAL TRANSPLANTATION

As previously reported, a significant proportion of pa­tients will develop irreversible renal functional impair­ment because of rapidly progressive glomerulonephritis early in the course of the disease (3-5, 7, 16). Although institution of appropriate therapy usually will induce complete remissions in these patients, initial severe renal damage can and does lead to end-stage renal failure, leav­ing a clinical situation of absence of disease activity in the presence of renal failure requiring hemodialysis. We have shown the feasibility of renal transplantation in such pa­tients (32). We have now successfully done renal trans­plantation in four patients who were in this category (Ta­ble 5). One patient died of an infection resulting from immunosuppressive therapy, and the other three patients are well after transplantation for periods after the trans­plant ranging from 16 months to 8 years.

Complications of Therapy COMPLICATIONS OF CYCLOPHOSPHAMIDE

The commonest toxic side effects of cyclophosphamide are marrow suppression, particularly leukopenia which may lead to a host defense defect and consequent infec­tious disease complication; hemorrhagic cystitis; hair loss; and gonadal dysfunction (33, 34). There have also been reports of neoplasms secondary to the oncogenic potential of the drug (35-38). In the present study, sever­al toxic side effects seen with the use of cyclophospha­mide deserve mention. In addition, the notable lack of certain side effects also deserves emphasis.

Hair loss was a rather insignificant problem in our pa­tients. At the cyclophosphamide dosage of 2 mg/kg body weight d, only a minimal degree of hair thinning was experienced by most patients, and the process was com­pletely reversible in all patients after discontinuation of the drug.

The lack of infectious complications of alternate-day corticosteroid regimens is well established (39) as is the avoidance of most infections due to cytotoxic regimens when the leukocyte count is maintained above an arbi­trary level of 3000 to 3500/mm3 with a neutrophil count of 1000 to 1500/mm3 (40) . Using this approach, infec­tions, particularly bacterial and fungal infections, were extraordinarily rare, with only one patient having bacterial sepsis. We have, however, seen an interesting susceptibility (9 episodes in 7 of 65 patients) to cutane­ous herpes zoster infection without visceral dissemination in patients who were in remission from Wegener's granu-

3 2 January 1983 • Annals of Internal Medicine • Volume 98 • Number 1

lomatosis, but were being maintained chronically on cy­clophosphamide with or without alternate-day predni­sone for variable periods of time ranging from 1 to 74 months (41).

Gonadal dysfunction remains a serious and seemingly invariable problem in our current regimen of daily cyclo­phosphamide, which is usually administered for years (mean, 40 months) . Clinical impressions point strongly towards a serious incidence of this problem among pa­tients treated chronically with cyclophosphamide. Wom­en who had not yet reached menopause invariably had some difficulty, usually in the form of oligomenorrhea or even amennorhea, while on cyclophosphamide. The re­versibility of this process has not been established due to the relatively small number of young women in the study who have had this complication and had therapy discon­tinued. With regard to the male patients, most had losses of libido and up to 2 5 % had various degrees of impo­tence, especially the older patients (40 years of age and older). It was very difficult to ascertain whether these effects resulted from the chronicity of their disease with its attendant depression, a direct gonadal suppressive ef­fect of the cyclophosphamide, or a combination of both. Testosterone levels and sperm counts in two men showed severe oligospermia and decreased serum testosterone levels after receiving cyclophosphamide for 2 to 4 years.

Hemorrhagic cystitis was a frequent toxic side effect of cyclophosphamide therapy. The severity of the cystitis varied greatly, and its presence did not always necessitate complete discontinuation of the drug. Twenty-seven of the 80 patients (34%) who received cyclophosphamide in the study developed some evidence of cystitis. It should be pointed out that although this number is clear­ly high, we were extremely attentive and alert to the ear­liest signs of cystitis. Patients who had signs and symp­toms of cystitis had a cystoscopic examination and a biopsy. Furthermore, microscopic hematuria in an asymp­tomatic patient in apparent remission of renal disease was considered cystitis until proved otherwise, and such pa­tients usually had a cystoscopic examination unless the hematuria cleared spontaneously and completely. The di­agnosis of cystitis was made from findings that ranged from erythema of the bladder mucosa in the presence of microscopic hematuria (mild cystitis) to mucosal telan­giectasia (moderate cystitis) to mucosal erosion and shedding (severe cystitis). Most patients diagnosed as having cyclophosphamide-induced cystitis had mild cys­titis, and only 3 of the 27 patients developed severe cysti­tis.

Nine of the 27 patients who developed this complica­tion had cyclophosphamide discontinued and were switched to a comparable dose of azathioprine. Four of the 27 patients had the cyclophosphamide discontinued without starting azathioprine, because they were at that point in the therapeutic protocol when the cyclophos­phamide would have been discontinued within a few months.

Of note are the 14 patients in whom cyclophosphamide was not discontinued, but was decreased (usually by 25 to 50 m g / d ) . All of these patients still showed evidence

of disease activity and were not yet in complete remis­sion. Fortunately, the cystitis was not severe in any of them. This latter group in whom cyclophosphamide was continued despite evidence of cystitis have been followed for irreversible bladder disease as well as bladder carcino­ma, and these complications have not occurred.

No long-term sequelae of cyclophosphamide-induced cystitis were seen in any patient. Bladder function has not been significantly compromised, nor have there been any cases of bladder carcinoma during long-term follow-up with urine cytologic examinations every 6 months and at least one follow-up cystoscopic examination in every pa­tient who developed cystitis. The three patients who had severe cystitis have no current problems related to the bladder.

A single instance of neoplasia was seen in our cyclo-phosphamide-treated patients during the 21-year period. A 48-year-old man had been maintained on cyclophos­phamide for an extended period because of smoldering disease and relapse when attempts were made to taper the drug. This patient developed a diffuse histiocytic lympho­ma during his ninth year of therapy.

COMPLICATIONS OF PREDNISONE THERAPY

There were very few serious and long-term complica­tions associated with prednisone therapy in these pa­tients. We feel that the major reason is because virtually all patients received daily corticosteroids for a limited period (a maximum of a few weeks) after which their corticosteroid regimen was given on alternate days. There was a single case of sepsis in a young man receiving cy­clophosphamide and in the process of converting from daily to alternate-day prednisone. This patient was re­ceiving daily corticosteroids when he had sepsis. Other complications included cataracts in three patients, severe osteoporosis in two patients who had received daily pred­nisone for several months before entrance in the study, diabetes mellitus in two patients, and psychosis in one patient.

Discussion

The present study represents our prospective experi­ence with 85 patients with well-documented Wegener's granulomatosis carefully followed for 21 years. This study firmly establishes several of the points that we re­ported almost 10 years ago with our original group of 18 patients (3) and adds the dimension of substantial long-term follow-up with regard to clinical and pathologic manifestations, response to therapy, maintenance of re­mission, incidence of relapse, and complications of thera­py. In addition, the study has allowed us to formulate and implement guidelines for initiation and modification of what has been shown to be an extremely effective ther­apeutic protocol.

The diagnosis of Wegener's granulomatosis was based on the findings of upper and lower respiratory tract in­volvement, renal disease, and variable degrees of dissemi­nated vasculitis involving other organ systems. With re­gard to the criteria for making the diagnosis of Wegener's granulomatosis, it should be pointed out that only 5 of

Fauci et al. • Wegener's Granulomatosis 83

our 85 patients did not have any form of upper airway involvement. Each of these patients had pulmonary dis­ease that was confirmed by open lung biopsy and a clini-copathologic picture in other organ systems that was in­dicative of Wegener's granulomatosis. Furthermore, 5 of 85 patients did not have recognizable lung disease. Each of these patients did have upper airway involvement shown by biopsy together with other findings compatible with Wegener's granulomatosis. Thus, in establishing the diagnosis of Wegener's granulomatosis, most patients had both lung and upper airway disease, and all patients had either one or the other. Finally, 8 5 % of patients had renal disease, putting them in the category of generalized Wegener's granulomatosis (3) . Given these statistics, we feel that to establish the definitive diagnosis of Wegener's granulomatosis, a patient should have clinical evidence of disease in at least two of the following three areas: upper airways, lung, and kidney. Biopsy results should show disease in at least one and preferably two of these organ systems.

The critical importance of establishing the diagnosis early in the course of the disease was emphasized in our original report (3) and is confirmed by the present long-term follow-up. Because there is a high rate of remission induction with the cyclophosphamide and alternate-day prednisone protocol, and because the most important and serious long-term complication of the disease is chronic renal failure due to renal damage that usually occurred before institution of therapy or early on in the induction phase of remission, early recognition and treatment of Wegener's granulomatosis is of utmost importance. Al­though some patients presented with fulminant disease, most patients had signs and symptoms for considerable periods before the diagnosis of Wegener's granulomatosis was made. The mean time from onset of first symptoms related to Wegener's granulomatosis to the establishment of the diagnosis was 8.3 ( ± 1.5) months. Earlier diagno­sis and appropriate treatment in some of these patients may have avoided the occurrence or extent of irreversible renal damage. Fortunately, the successful use of renal transplantation in this disease has been feasible as a treat­ment for chronic renal failure (32, 42).

Complete remissions were induced and maintained in 79 of 85 patients for a remission-induction rate of 9 3 % . The entire study group was followed at N I H for 51 ( ± 4.3) months. Seventy-five patients are still alive, and the mean duration of time off all therapy is 35.3 ( i t 6.3) months. Of particular note is the fact that only six pa­tients in the study died of active disease. Thus, the re­sponse to therapy in this group is striking.

Of note was the fact that 25 patients who achieved remission also had some degree of relapse. Twenty-four of these patients were promptly reinduced into remission by increasing the dose of cyclophosphamide and predni­sone. Only three patients had relapses after their therapy had been discontinued, and all three of these patients also had reinduction of remission with resumption of therapy. Twenty-two of the 25 patients who had relapses were having their therapy tapered with the intent to discontin­ue all treatment. We have suggested previously (4, 5, 7,

8) that patients be treated for at least 1 full year after they are judged to be in complete remission. We recom­mend treating for that year and then tapering the cyclo­phosphamide dose (as well as the corticosteroid dose if they are still receiving this latter drug at the time) grad­ually over several months. Because the potential for re­lapse is substantial, gradual tapering after the patient had been in remission for 1 full year usually allows for a smooth transition to discontinuation, and relapses, when they occur, are usually blunted because of the therapy the patients are still receiving.

Although the apparent efficacy of cyclophosphamide in the treatment of Wegener's granulomatosis has been emphasized (3-5) and now confirmed in this study, the question has been raised as to the relative efficacy of oth­er cytotoxic agents such as azathioprine and chlorambu­cil. Previous studies have suggested that neither of these drugs are as effective as cyclophosphamide in the treat­ment of generalized Wegener's granulomatosis (4, 12, 31). However, a controlled trial has not been done. Evi­dence from the present study strongly suggests that aza­thioprine is not as effective as cyclophosphamide in the induction of remission in Wegener's granulomatosis. On the other hand, azathioprine may be an acceptable alter­native for maintenance therapy in patients who have achieved remission on cyclophosphamide and can no longer be given the drug. Such was the case with nine patients who had achieved remission on cyclophospha­mide and developed drug-induced cystitis. Only one of the nine patients relapsed while receiving azathioprine. Although azathioprine is not nearly as effective as cyclo­phosphamide in the induction of remission of active dis­ease in Wegener's granulomatosis, it may be useful in maintaining remission during the tapering period in pa­tients who cannot tolerate cyclophosphamide.

Despite the excellent results with the cyclophospha­mide and alternate-day prednisone protocol, attention must be paid to the actual and potential toxic side effects of these drugs, especially cyclophosphamide.

With regard to neutropenia, we feel that one of the most important aspects of our successful use of cyclo­phosphamide was maintaining the leukocyte count above a neutropenic level by frequently adjusting the dose as the leukocyte count decreased. By using this approach, there was only one episode of acute sepsis related to cy­clophosphamide treatment, and this was in a patient also receiving a daily dose of corticosteroids. We did, howev­er, see a relatively high incidence of herpes zoster infec­tions in the group (41). However, the infection did not viscerally disseminate in any of the patients.

Cystitis was a major problem, and the high incidence (34%) was probably due to the true significant incidence together with the fact that we were alert to the complica­tion and did cystoscopic examinations in patients with unexplained hematuria, even in patients without signifi­cant symptoms. Fortunately, there were no long-range sequelae of cystitis in any patients; specifically, no func­tionally significant bladder fibrosis and no bladder tumors. Nonetheless, the high incidence of cystitis is dis­turbing, and evidence of later complications will be care-

g 4 January 1983 • Annals of Internal Medicine • Volume 98 • Number 1

fully looked for. Gonadal dysfunction was also a side effect of chroni­

cally administered cyclophosphamide therapy. We are currently beginning oral contraceptives in menstruating women together with the institution of cyclophospha­mide because of recent evidence that ovarian dysfunction may be avoided by pharmacologically suppressing ovula­tion (43). Finally, one of our patients developed a lym­phoma while receiving cyclophosphamide for a pro­longed period of time. Recent reports have shown that oncogenic effects can occur with cyclophosphamide (35-38). Although this was a rare event occurring in only 1 of 85 patients over a 21-year period and could be explained by chance, we must presume that the development of the lymphoma was related to the cyclophosphamide therapy.

In conclusion, the present study reports the prospec­tive experience with 85 pateints with Wegener's granulo­matosis followed over a 21-year period, and establishes the efficacy of the treatment regimen of chronic low-dose cyclophosphamide together with alternate-day predni­sone in inducing long-term remissions. Careful attention to adjusting the dose of cyclophosphamide in accordance with the resulting leukopenia as well as the early conver­sion to an alternate-day prednisone regimen has been of extreme importance in the avoidance of the host defense defects that are usually attendant with the use of such regimens. This treatment has allowed a high rate of long-term remissions without life-threatening complications in what was once a fatal disease. ACKNOWLEDGMENTS: The authors thank Dr. James E. Balow for pro­viding excellent renal consultation on these patients, and Dr. Thomas Law-ley, National Cancer Institute, for doing the determinations of circulating immune complexes.

• Requests for reprints should be addressed to Anthony S. Fauci, M.D.; Building 10, Room 11B-13, National Institutes of Health; Bethesda, MD 20205.

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