501

WEGENER’S GRANULOMATOSIS LONG-TERM FOLLOWUP OF PATIENTS TREATED W I T H CYCLOPHOSPHAMIDE MICHAEL J. REZA, LESLIE DORNFELD, LEONARD S. GOLDBERG, RODNEY BLUESTONE, and CARL M. PEARSON Ten patients with Wegener’s granulomatosis were treated with cyclophosphamide and followed for periods up to 7 years. I n all cases cyclophosphamide induced complete remissions. T h e mean duration of remission (to date) was 38 months. Six patients have been in remission for a mean of 46 months after cyclophosphamide was discontinued; 2 have been disease-free for 7 years. Of the 10 patients treated, only 1 relapsed and she responded to a second course of cyclophosphamide. These results indicate that cyclophosphamide is the drug of choice in Wegener’s granulomatosis. T h e long-term effectiveness of this drug suggests that it may induce permanent remissions in certain patients with Wegener’s granulomatosis.

From the Department of Medicine, University of California at Los Angeles School of Medicine, Los Angeles, California 90024, and the Wadsworth VA Hospital, Los Angeles, California 90073. Supported in part by grants from the USPHS (GM 15759) and the Kroc Foundation. VA Project No. 1008-03. Michael J. Reza, M.D.: Resident in Internal Medicine; Leslie Dornfield, M.D.: Clinical Assistant Professor of Medicine; Leonard S. Goldberg, M.D.: Associate Professor of Medicine; Rodney Bluestone, M.B., M.R.C.P.: Associate Professor of Medicine; Carl M. Pearson, M.D.: Professor of Medicine. Address reprint requests to Dr. Michael J. Reza, U.C.L.A. Medical Center, 10833 Le Conte Avenue, Los Angeles, California 90024. Submitted for publication December 13, 1974; accepted February 14, 1975. Arthritis and Rheumatism, Vol. 18, No. 5 (September-October 1975)

Prior to the use of immunosuppressive agents, Wegener’s granulomatosis (WG) appeared to be a uniformly fatal disorder. In 1958, the average survival time in patients with this disease was 5 months (1). During the 1960s, the prognosis appeared to improve when selected patients were treated with a variety of cytotoxic agents including nitrogen mustard, methotrexate, and azatliioprine (2). More recently, dramatic responses to cyclophosphamide have been described in sul>jectswith WG (3). However, with the exception of a recent report from the National Institutes of Health (4), no information is available regarding the long-term prognosis of this disorder following treatment with cyclophospliamide. This paper describes the long-term followup of 10 patients with WG who were treated with cyclophosphamide.

MATERIALS A N D METHODS T e n patients with WG were initially seen a n d followed a t either t h e U CLA Medical Center or the Wadsworth Veterans Hospital. T h i s g r o u p represents all patients with WG seen a t these two hospitals between 1967 a n d 1974. All h a d been treated with cyclophosphamide, a n d each hatl received prednisone previously without benefit. No o t h er immunosuppressive agents were administered to these patients. Fo u r of the cases hatl been previously reported (3). Clinical Features. T h e patient g r o u p consisted of 7 males a n d 3 females; the median age a t the time of diagnosis was 41 years with a range f r o m 18 to 71 years. The diagnostic criteria used i n the present study were similar or identical to those described by Fauci and Wolff (5).

REZA E T AL

502

Table 1. Clinical Features in I0 Patients with Wegener’s Granulomatosus

Age at Patient Diagnosis

Sex

Initial Symptoms

52 49 47

F M M M M

8

36 18 71 21 45

9

23

M

10

47

F

Rhinorrhea, cough, fever Sinusitis, headache, obtundation Rhinorrhea, otalgia, deafness, facial palsy Fcver, rhinorrhea, weight loss Sinusitis, otitis, weight loss Rhinorrhea, hemoptysis Rhinorrhea, polyarthritis, rash Fever, night sweats, headache, confusion Fever, night sweats, hemoptysis, polyarthralgias, weight loss Rhinorrhea, otalgia, deafness, fever

1

2 3 4 5 6

I

M F M

Table 1 shows the prominent presenting symptoms. Symptoms attributable to involvement of the nasopharyngeal and paranasal sinuses were the most common. T a b l e 2 outlines the major organ systems involved i n these patients. All had nasopharyngeal a n d pulmonary involvement and all but 1 had renal dysfunction. Hematuria a n d proteinuria were present i n the 9 subjects with renal involvement; 6 of these had diminished creatinine clearances. Eight of the 10 showed symptoms o r signs consistent with impairment of the nervous system (peripheral neuropathy, cranial nerve palsy, pseudotumor cerebri, obtundation). Five subjects had ocular involvement including proptosis, papilledema, granulomatous abscess, and episderitis. All patients had nodular inflltrates o n chest x-rays, and anemia, leukocytosis, and markedly elevated sedimentation rates. T h e diagnosis i n all subjects was confirmed by renal, pulmonary, or nasopharyngeal biopsies. Cyclophosphamide Therapy. All patients were receiving varying doses of prednisone when initially seen; the dose was gradually tapered over several months. Cyclophosphamide was given intravenously in 6 patients initially, followed i n 7 to 10 days by orally administered cyclophosphamide. Initially the remaining 4 subjects were treated orally with cydophosphamide. Kesponse to cyclophospha-

mide was assessed by both clinical and laboratory parameters. Once the disease was shown to be i n remission by these parameters, the dose of cyclophosphamide was slowly tapered. T h e dose and duration of treatment are listed i n T a b l e 3. T h e average oral dose was 117 mg daily a n d the mean duration of therapy was 17 months. Leukopenia and secondary infections were not observed during treatment. One patient developed cystitis and 1 had a n onset of ammennorrhea while o n therapy.

RESULTS Tables 4 and 5 show the effects of therapy with cyclophosphamide i n 10 patients with WG. A complete remission occurred in all patients, usually within 4 to 6 months. Pulmonary and nasopharyngeal lesions resolved in every patient and the hematuria and proteinuria present in 9 patients disappeared. T h e creatinine clearance that was diminished in 6 patients either returned to normal or was markedly improved following treatment. T h e mean duration of remission (to date) was 38 months. I n 6 patients cyclophosphamide has been discontinued (mean duration: 46 months) with no evidence of relapse i n 5. Patients 2 and 4 have been in total remission for 7 years. Patient 7 recently was hospitalized with hematuria and abdominal pain; a renal biopsy was nondiagnostic, but cyclophosphamide was reinstituted with subsequent resolution of hematuria. Three other patients, 8, 9, and 10, diagnosed in the past 16 months are still receiving therapy but are currently i n remission. Typical responses to cyclophosphamide are shown i n Figures 1 and 2 . Patient 1 presented with clense pulmonary infiltrates; 4 months following institution of therapy the pulmonary lesions resolved (Figures 1 and 2). Patient 5 developed renal failure

Table 2. Organ System Involvement in 10 Patients with Wegener’s Granulomatosus Patient 1

2 3 4 5 6

7 8 9 10

Pharynx

Paranasal Sinuses

+ ++ ++ + ++ ++ +++ + + +++

+ +++ ++ +++ + ++ ++ ++ +++

+ = mild. ++ = moderate. +++ = severe. ++++ = extremely severe.

Ears

Eyes

Lungs

+ -

+++ ++++ +++ -

+++ +++ ++ ++ +++ +++ +++ +++ +++

++ ++ ++ -

+++

-

+

-

-

+

+++

Kidney ++f

+ +

+++ +++ ++ + +++ +

Skin

-

Joint

-

-

++ -

+++ -

++ ++ -

-

-

-

Nervous System

+ +++ + +++ + +++ +++ + -

503

WEGENERS GRANULOMATOSIS

Fig 1. Patient I . Chest x-ray prior to cyclophosphamide shows dense pulmonary infiltrates.

Table 3. Cyclophosphamide Therapy in 10 Patients with Wegener's Granulomatosus Patient

Initial IV Therapy (mg/kg)

Duration (mo)

Maximum Daily Dose (mg)

Average Daily Dosc (mg)

1

15 mg/kg X 4 days

6 11

10 16 11

150 200 150 150 150 150 75

130 175 80 100 150 65 67.5

15

150

105

15 10

100

100

200

200

2

-

39 32

10 mg/kg X 4 days

-

8 9 10

8 mg/kg X 2 days then 4 mg/kg X 2 days 10 mg/kg X 3 days then q week X 2 5 mg/kg X 2 days 5 mg/kg X 2 days

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504

Fig 2. Patient 1 . Chest x-day obtained after 3 months resolution of infiltrates.

with an active urinary sediment and a rising creatinine despite therapy with prednisone; after 6 months of cyclopliosphamide the serum creatinine (Figure 3) and other parameters of renal function returned to normal. I n summary, 9 of the 10 patients with WG treated with cyclophosphamide remain in remission without evidence of reactivation of disease. Patient 7 appeared to relapse 30 months after cyclophosphamide was discontinued but she responded rapidly to reinstitution of therapy.

of

cyclophosphamide shows dramatic

3 0-

2 5-

2 0SERUM CREAT~N~NE mq% 15-

IO-

T h e results of this stutly confirm [lie effectivencss of c)clol,lio\l,li;iinitle in p;itiettts w i t l i \V(; ;ind . clearly clemonstratc the long-term benefits of this therapy. I n every instance cyclopliosp1i;iniitle induced complete resolution of the disease with ii mean tlura-

WEGENERS DISEASE Cose#S Y-I8

PREDklSONE mpld

-

;; CYCLOPHOSPHAMIDE

ka,b,

I

505

WEGENER’S GRAN ULOMATOSIS

Table 4. Z.ongternz Followup on Patients with Generalized M’ege?rer’\ Grrinulotttatosiis Trented with Cyclophosphnmide Total patients Died Complete remission Relapses In remission (still on therapy) In remission (off therapy)

10 0 10 1

In remission (lost to followup)

1

3 6

Mean time from diagnosis: 50 months (range: 10-116 months)

>.lean time on therapy: 13 months (range: 10-15 months) Mean time on therapy before discontinuance: 14 months (range: 8-32 months) Mean time off therapy: 46 month5 (range: 12-80 months) On therapy: 39 months In remission: 37 months

therapy was stopped, but she responded well to a second course of therapy. Similar results were recently reported by WolR et al (4), who noted excellent responses to cyclophosphamide in 15 of I 7 patients with WG; 2 subjects died despite therapy. (Three additional patients died before adequate therapy could be instituted.) Of the remaining 15, 7 remained i n remission following cessation of therapy, and 8 are in remission on therapy. Three of these patients relapsed after cyclophosphamide was discontinued but responded to reinstitution of therapy. T h e mean duration of remission in the surviving patients was 34 months; similarly, the mean duration of remission in our patients was 38 months. Combining the patient group from the National Institutes of Health and from UCLA, it seems clear that cyclophosphamide is the therapeutic agent of choice in WG; in certain patients the length of remission following therapy is of sufficient duration to suggest possible cure of the underlying disorder. T h e optimum dose and duration of therapy with cyclophosphamide in W G cannot be stated with absolute certainty. Nor is it possible to predict which patients will remain in long-term remission following cessation of therapy. I n the study reported here, 6 of

tlie I0 patients were initially given cyclophosphamide, 4-15 mg/kg intravenously, followed in 7-10 days by orally administered cyclophospliamide, 1-2 mg/kg. These patients were for the most part critically ill at the time of admission. I n the N I H study many of the patients were given the drug orally, 1-2 mg/kg, although several ot tlie very ill were initially treated wi tli cyclophosphamide intravenously. T h e duration of therapy in patients who have remained in remission following cessation of cyclophospliamide has varied considerably; in our patients the length of therapy ranged from ti to 39 months, whereas tlie duration in tlie NIH group was 3 to 61 months. In the present series long-term remission did not appear to be a function of dose or duration of therapy. However, the single patient who relapsed had received one of the lowest average daily closes of cyclophosphamide. From these observations the following treatment in WG is recommended: a) Critically ill patients, such as those with fulminant renal disease, should receive cyclophospliamide, 5-1 0 mg/kg intravenously for 2-3 day>, followed in 7-10 days (depending on WBC count) by orally administered cyclopliospliamitle, 1-2 mg/kg. b) Those not acutely ill may be treated initially with oral therapy, 1-2 mg/kg, because most of

Table 5. Followup Data on 10 Patients with Wegener’s Granulonratosus Treated with Cycloplrospharriide

Patient

Duration of Therapy (mo)

Time Since Diagnosis (mo)

Time off Therapy (mo)

6 11

85 116 40

56 80

97

58

10

48

16 11 15

29

39 12 30

1

2 3

4 5 6

7 8

9 10 *Lost to followup.

39 32

41

15

15 16

10

10

*

0

0 0

Total Time in Remission

(4 57 84

37 84 40

Total Time in Remission off Therapy (mo) 56 80

*

58

39

23

12

30 10 10 6

30 0 0 0

REZA E T AL

these patients will respond to oral cyclophosphamide Patients should be maintained on treatment for 12 to 18 months after all evidence of the disease has subsided (4). Periodic followups are essential because certain patients will relapse and these will usually respond to second courses of treatment with cyclophosphamide. T h e mechanism by which cyclophosphamide induces remissions in Wegener’s granulomatosis is not known. Although this agent is a known immunosuppressive, there is no definite evidence showing that WG is an immune-mediated disorder. Whether or not the immunosuppressive properties of cyclophosphamide relate to its therapeutic effectiveness in WG remains unclear.

REFERENCES 1. Walton EW: Giant-cell granuloma of the respiratory

2.

3.

4. 5.

tract (Wegener’s granulomatosis). Br Med J 2:265-270, 1958 Aldo MA, Benson MD, Comerford FR, et al: Treatment of Wegener’s granulomatosis with immunosuppressive agents. Arch Intern Med 126:298-305, 1970 Novak SN, Pearson CM: Cyclophosphamide therapy in Wegener’s granulomatosis. N Engl J Med 284:938-942, 1971 Wolff SM, Fauci AS, Horn RG, et al: Wegener’s granulomatosis. Ann Intern Med 81:513-525, 1974 Fauci AS, Wolff SM: Wegener’s granulomatosis: studies in eighteen patients and a review of the literature. Medicine 52:535-561, 1973