journal of Internal Medicine 1992 : 232 : 279-282
Case report
Pulse cyclophosphamide therapy in Wegener’s granulomatosis : a pilot study A. A. DROSOS, L. I. SAKKAS, A. GOUSSIA, K. C. SIAMOPOULOS & H. M. MOUTSOPOULOS Prom the Department o/ Internal Medicine, School of Medicine. University o/ loannina. loannina. Greece
Abstract. Drosos AA. Sakkas LI, Goussia A, Siamopoulos KC. Moutsopoulos HM (Department of Internal Medicine, School of Medicine, University of loannina, Greece). Pulse cyclophosphamide therapy in Wegener’s granulomatosis : a pilot study. journal of lnternal Medicine 1992: 232: 279-282. Five patients with Wegener’s granulomatosis (WG) have been treated with 6- to 8monthly pulses of intravenous cyclophosphamide (CP) and glucocorticoids in an open pilot study. One patient achieved complete remission sustained during 30 months of follow-up: one patient had features of active disease after 28 months of remission: two patients after an initial remission had an exacerbation of the disease and received continuous oral administration of CP. and one patient required continuous oral CP to control the symptoms. These results suggest that this regimen may not achieve a high degree of sustained remission in patients with WG.
Keywords: cyclophosphamide, pulse therapy, Wegener’s granulomatosis.
Introduction Wegener’s granulomatosis (WG) is a chronic systemic necrotizing vasculitis that affects the upper and lower airways and the kidneys [l]. The prognosis was very poor until the introduction of cyclophosphamide (CP) therapy [2-51. Oral CP is effective, but requires long-term treatment which can result in serious side-effects [6, 71. On the other hand, intravenous pulse (ivp) CP has been shown to be very effective and less toxic in the treatment of lupus nephritis [8]. Furthermore, ivp-CP was shown to be effective in some cases of polymyositis [ 9 , 1 0 ] and polyarteritis nodosa [11]. The aim of this study was to investigate the efficacy, safety and tolerance of ivp-CP in WG patients. Abbreviations: WG = Wegener’s granulornatosis. CP = cyclophospharnide. ANCA = aptineutrophil cytoplasmic antibodies, OLB = open lung biopsy, P@ = percutaneous kidney biopsy. ivp = intravenous pulse.
Patients and treatment Patients Five patients, all men, were presented or referred to our Department for further evaluation. The diagnosis of WG was based on the clinical picture, chest X-ray and CT-scan findings, positive antineutrophil cytoplasmic antibodies (ANCA) a n d compatible histopathological findings of clinically involved organs [l]. Infection was ruled out by repeated blood a n d urine cultures. The clinical profile of our patients is shown in Table 1.
Treatment Patients received 6 to 8 doses of ivp CP (0.5-1 g m-’) once a month. They also received prednisolone 0.5 mg kg-’ d-’ orally, upon first entering the study. The prednisolone dose was gradually reduced after the first 2 months of treatment. Complete blood counts were performed 7 and 1 2 d after each iv pulse 2 79
Complete remission
Complete remission
Otitis, sinusitis, oral ulcers, nasal ulcers, anaemia. haemoptysis. cough, crescentic glomerulonephritis
Haemoplysis. sinusitis, nasal ulcers, pulmonary infiltration, pericardiac effusion, central nervous system, anaemia, skin vasculitis. gut performation, kidneys
Right tympanic membrane perforation, epistaxis. arthralgias. pulmonary cavitating infiltrations. kidneys, intestinal haemorrhage
3
4
5
* Oral cyclophosphamide. 2 mg kg-' d-' plus prednisolone
Complete remission
Complete remission
Deterioration*
Complete rem iss ion
Complete remission
Sinusitis, myalgias. arthralgias. otitis, oral ulcers, nasal ulcers, pulmonary cavitating lesions, anaemia, active urine sediment, proteinuria
2
No improvement
Complete remission
Complete remission
9 months
Arthralgias, myalgias. pleural effusion, pulmonary cavitating lesions. segmental necrotizing glomerulonephritis. anaemia
6 months
1
Organ involvement Case and/or manifestations
Outcome at
Table 1 . Organ involvement and outcome of patients with WG
Relapse*
Stable
Relapse*
Complete remission
Complete remission
1 2 months
Remission
Improvement
Marginal improvement
Complete remission
Complete remission
16 months
-
-
-
Stable
Complete remission +relapse*
Complete remission
Stable
Complete remission
30 months
Complete remission
24 months
Nasal ulcers and bleeding, intestinal bleeding, haematuria. TESR. TcANCA
Intestinal perforation fever. anaemia TESR
Anaemia, ?serum creatinine. proteinuria tESR, TcANCA
Haematuria, ?serum creatinine, tESR TANCA
-
Clinical and/or laboratory findings at relapses
e
c:
v3
0
v3
0
P
U
? ?
PULSE CYCLOPHOSPHAMIDE IN WEGENER’S GRANULOMATOSIS
to assess drug-induced side-effects. After the completion of iv pulses of CP and in the absence of active disease, patients received no more CP. Patients who subsequently showed features of active disease received oral CP, 2 mg kg-’ d-’, and prednisolone (Table 1). Urine collections for cytological examination were made at 2-month intervals during the follow-up period.
281
an episode of high fever and confusion (lumbar puncture revealed no signs of inflammation), necrotic skin vasculitis over the gluteal area, and anaemia. The patient’s kidney function deteriorated, and he underwent surgery for small bowel perforation. His prednisolone dose was gradually reduced to 1 6 mg daily, and oral CP was instituted. The patient subsequently remained in reasonably good health, with normal ESR and cANCA positive at a titre of 1/160.
Case 1 In this 47-year-old man, ANCA were positive at presentation at a titre of 1/320 with a granular pattern [12]. Chest X-rays revealed left pleural effusion and lung parenchymal cavities. PPD was negative. Open lung biopsy (DLB) revealed necrotizing granulomatous vasculitis, and percutaneous kidney biopsy (PKB) revealed segmental necrotizing glomerulonephritis. Case 2 This 17-year-old man had ANCA positive at a titre of 1/640 with a granular pattern at presentation. Chest CT-scan revealed pulmonary cavitating lesions bilaterally. Nasal mucosal biopsy and OLB revealed necrotizing granulomatous vasculitis. Case 3 This 73-year-old man had ANCA positive at a titre of 1/640 with a granular pattern at presentation. Nasal mucosal biopsy revealed necrotizing granulomatous vasculitis and PKB revealed crescentic glomerulonephritis. Case 4 In this 43-year-old man, cANCA were positive at a titre of 1/160 at presentation. CT-scan of frontal sinuses revealed a polypoid mass with bone erosions, and nasal mucosal biopsy revealed granulomatous inflammatory formation without vasculitis. Two weeks after institution of iv CP pulses, the patient experienced acute abdominal pain, mouth ulcers, haemoptysis and dyspnoea. Chest X-ray and CT-scan revealed peribronchial infiltration on the right side with small pericardial effusion. Three pulses of 1 gr iv methylprednisolone were added to his treatment regimen. Over the next few months, the patient had
Case 5 In this 41-year-old man the right tympanic membrane and nasal septum were found to be perforated at presentation. Chest X-rays and CT-scan revealed multiple pulmonary infiltrations with cavities in the left lung. PPD was positive. Nasal mucosal biopsy and OLB revealed granulomatous inflammation and stain for M . tuberculosis and culture were negative. The patient received isoniazid prophylaxis in addition to his treatment regimen.
Discussion The present study is a preliminary pilot investigation to assess the efficacy of intermittent high-dose intravenous cyclophosphamide treatment in WG. The major advantage of ivp-CP treatment is a reduction in long-term drug-related toxicity compared to a low-dose daily regimen [8]. However, the efficacy of ivp-CP in WG compared to that of low-dose daily cyclophophamide is not certain. Two of our patients experienced complete remission with ivp-CP treatment, and they sustained a drug-free remission 24 months after the cessation of treatment. At that time, however, one of these two patients developed features of active disease. Two patients, after an initial remission, experienced recurrence of active features of the disease 4 and 12 months, respectively, after the pulse treatment had stopped. These patients regained remission with oral low-dose CP. In one patient, ivp-CP was totally ineffective, and the patient achieved and sustained improvement on a daily lowdose regimen. These results are in agreement with the findings of two previous studies [13,14] which reported high relapse rates. In contrast, Haubitz et aJ. [15] have reported similar relapse rates in patients treated with ivp-CP and in those treated with a lowdose daily cyclophosphamide (2/8 and 3/15, respectively).
282
A. A. DROSOS et al.
These differences may be explained by the different protocols used in the ivp-CP administration and corticosteroid administration. It is also possible that there is a subset of WG which is responsive to pulse CP treatment. In summary, our results suggest that the ivp-CP treatment may not achieve a high degree of sustained remission in WG. Furthermore, carefully planned clinical trials are needed to define the role of ivp-CP in the treatment of WG patients.
References Fauci AS, Haynes BF. Katz P. The spectrum of vasculitis: clinical, pathologic. immunologic and therapeutic considerations. Ann Intern Med 1978: 89: 660-76. Hollander D. Manning L. The use of alkylating agent in the treatment of Wegener's granulomatosis. Ann Intern Med 1967: 67: 393-8. Fauci AS, Wolfl SM. Wegener's granulomatosis: studies in eighteen patients and a review of the literature. Medicine 1973: 52: 535-61. Keza M J . Dornfeld L. Goldberg LS, Bluestone P. Pearson CM. Wegener's granulomatosis : long-term follow-up of patients treated with cyclophosphamide. Arthritis Rheum 1975: 18: 501-6. Fauci AS. Haynes BF. Katz P. WolK SM. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ariri Interri Med 1 9 8 3 : 98: 76-85.
6 Decker JC. Toxicity of immunosuppressive drugs in man. Arthritis Rheum 1973: 16: 89-91. 7 Schein PS. Wino Kur SH. Immunosuppressive and cytotoxic chemotherapy : long-term complications. Ariri lriterri Med 1 9 7 5 : 82: 84-95. 8 Ballow JF, Austin HA 111. Tsokos GC, Antonovych ' I T , Steinberg HD. Klippel JH. Lupus nephritis. Arin Iritcrri ,tied 1 9 8 7 : 106: 79-94. 9 Bombardieri S. Hughes GRV, Neri R. Del Bravo D. Del Bono I,. Cyclophosphamide in severe polymyositis. Imicet 1989 : 1 : 1138-9. 10 Leroy JP. Drosos AA. Yiannopoulos DI. Youinou 1'. Moutsopoulos HM. Intravenous pulse cyclophosphamide therapy in myositis and Sjogren's syndrome. Arthritis Kheitrri 1990: 3 3 : 1579-81. 11 Fort JG, Abraxo JL. Reversal of progressive necrotiaing vasculitis with intravenous pulse cyclophosphamide and methylprednizone. Arthritis Rheurn 1988 : 31 : 1 194-8. 12 Nolle B, Specks V. Ludemann J, Rohrbach MS, Deremec RA. Gross WL. Anticytoplasmic autoantibodies : their immunodiagnostic value in Wegener's granulomatosis. Ariri lritcrri Med 1 9 8 9 : 111: 2 8 4 0 . 1 3 Hoffman GS. Leavitt RY, Fleisher TA. Minor JR, Fauci AS. Treatment of Wegener's granulomatosis with intermittent high-dose intravenous cyclophosphamide. Arri 1 Mrd 1 9 9 0 : 89: 403-10. 14 Ulmer M. Reinhold-Keller E. Gross WL. Alternative treatment strategies in Wegener's granulomatosis: first results of a prospective study. APMIS 1 9 9 0 : 98 (Suppl. 19): 5 1 . 15 Haubitz M. Frei U. Rother U. Brunkhorst R. Koch KM. Cyclophosphamide pulse therapy in Wegener's granulomatosis. Nephrol Dial Transplant 1991 ; 6: 531-5.
Received 22 November 1991. accepted 27 January 1992.
Correspondence: A. A. Crosos. MD. Department of Internal Medicine, University of Ioannina. 451 1 0 Ioannina. Greece.
Case report
Pulse cyclophosphamide therapy in Wegener’s granulomatosis : a pilot study A. A. DROSOS, L. I. SAKKAS, A. GOUSSIA, K. C. SIAMOPOULOS & H. M. MOUTSOPOULOS Prom the Department o/ Internal Medicine, School of Medicine. University o/ loannina. loannina. Greece
Abstract. Drosos AA. Sakkas LI, Goussia A, Siamopoulos KC. Moutsopoulos HM (Department of Internal Medicine, School of Medicine, University of loannina, Greece). Pulse cyclophosphamide therapy in Wegener’s granulomatosis : a pilot study. journal of lnternal Medicine 1992: 232: 279-282. Five patients with Wegener’s granulomatosis (WG) have been treated with 6- to 8monthly pulses of intravenous cyclophosphamide (CP) and glucocorticoids in an open pilot study. One patient achieved complete remission sustained during 30 months of follow-up: one patient had features of active disease after 28 months of remission: two patients after an initial remission had an exacerbation of the disease and received continuous oral administration of CP. and one patient required continuous oral CP to control the symptoms. These results suggest that this regimen may not achieve a high degree of sustained remission in patients with WG.
Keywords: cyclophosphamide, pulse therapy, Wegener’s granulomatosis.
Introduction Wegener’s granulomatosis (WG) is a chronic systemic necrotizing vasculitis that affects the upper and lower airways and the kidneys [l]. The prognosis was very poor until the introduction of cyclophosphamide (CP) therapy [2-51. Oral CP is effective, but requires long-term treatment which can result in serious side-effects [6, 71. On the other hand, intravenous pulse (ivp) CP has been shown to be very effective and less toxic in the treatment of lupus nephritis [8]. Furthermore, ivp-CP was shown to be effective in some cases of polymyositis [ 9 , 1 0 ] and polyarteritis nodosa [11]. The aim of this study was to investigate the efficacy, safety and tolerance of ivp-CP in WG patients. Abbreviations: WG = Wegener’s granulornatosis. CP = cyclophospharnide. ANCA = aptineutrophil cytoplasmic antibodies, OLB = open lung biopsy, P@ = percutaneous kidney biopsy. ivp = intravenous pulse.
Patients and treatment Patients Five patients, all men, were presented or referred to our Department for further evaluation. The diagnosis of WG was based on the clinical picture, chest X-ray and CT-scan findings, positive antineutrophil cytoplasmic antibodies (ANCA) a n d compatible histopathological findings of clinically involved organs [l]. Infection was ruled out by repeated blood a n d urine cultures. The clinical profile of our patients is shown in Table 1.
Treatment Patients received 6 to 8 doses of ivp CP (0.5-1 g m-’) once a month. They also received prednisolone 0.5 mg kg-’ d-’ orally, upon first entering the study. The prednisolone dose was gradually reduced after the first 2 months of treatment. Complete blood counts were performed 7 and 1 2 d after each iv pulse 2 79
Complete remission
Complete remission
Otitis, sinusitis, oral ulcers, nasal ulcers, anaemia. haemoptysis. cough, crescentic glomerulonephritis
Haemoplysis. sinusitis, nasal ulcers, pulmonary infiltration, pericardiac effusion, central nervous system, anaemia, skin vasculitis. gut performation, kidneys
Right tympanic membrane perforation, epistaxis. arthralgias. pulmonary cavitating infiltrations. kidneys, intestinal haemorrhage
3
4
5
* Oral cyclophosphamide. 2 mg kg-' d-' plus prednisolone
Complete remission
Complete remission
Deterioration*
Complete rem iss ion
Complete remission
Sinusitis, myalgias. arthralgias. otitis, oral ulcers, nasal ulcers, pulmonary cavitating lesions, anaemia, active urine sediment, proteinuria
2
No improvement
Complete remission
Complete remission
9 months
Arthralgias, myalgias. pleural effusion, pulmonary cavitating lesions. segmental necrotizing glomerulonephritis. anaemia
6 months
1
Organ involvement Case and/or manifestations
Outcome at
Table 1 . Organ involvement and outcome of patients with WG
Relapse*
Stable
Relapse*
Complete remission
Complete remission
1 2 months
Remission
Improvement
Marginal improvement
Complete remission
Complete remission
16 months
-
-
-
Stable
Complete remission +relapse*
Complete remission
Stable
Complete remission
30 months
Complete remission
24 months
Nasal ulcers and bleeding, intestinal bleeding, haematuria. TESR. TcANCA
Intestinal perforation fever. anaemia TESR
Anaemia, ?serum creatinine. proteinuria tESR, TcANCA
Haematuria, ?serum creatinine, tESR TANCA
-
Clinical and/or laboratory findings at relapses
e
c:
v3
0
v3
0
P
U
? ?
PULSE CYCLOPHOSPHAMIDE IN WEGENER’S GRANULOMATOSIS
to assess drug-induced side-effects. After the completion of iv pulses of CP and in the absence of active disease, patients received no more CP. Patients who subsequently showed features of active disease received oral CP, 2 mg kg-’ d-’, and prednisolone (Table 1). Urine collections for cytological examination were made at 2-month intervals during the follow-up period.
281
an episode of high fever and confusion (lumbar puncture revealed no signs of inflammation), necrotic skin vasculitis over the gluteal area, and anaemia. The patient’s kidney function deteriorated, and he underwent surgery for small bowel perforation. His prednisolone dose was gradually reduced to 1 6 mg daily, and oral CP was instituted. The patient subsequently remained in reasonably good health, with normal ESR and cANCA positive at a titre of 1/160.
Case 1 In this 47-year-old man, ANCA were positive at presentation at a titre of 1/320 with a granular pattern [12]. Chest X-rays revealed left pleural effusion and lung parenchymal cavities. PPD was negative. Open lung biopsy (DLB) revealed necrotizing granulomatous vasculitis, and percutaneous kidney biopsy (PKB) revealed segmental necrotizing glomerulonephritis. Case 2 This 17-year-old man had ANCA positive at a titre of 1/640 with a granular pattern at presentation. Chest CT-scan revealed pulmonary cavitating lesions bilaterally. Nasal mucosal biopsy and OLB revealed necrotizing granulomatous vasculitis. Case 3 This 73-year-old man had ANCA positive at a titre of 1/640 with a granular pattern at presentation. Nasal mucosal biopsy revealed necrotizing granulomatous vasculitis and PKB revealed crescentic glomerulonephritis. Case 4 In this 43-year-old man, cANCA were positive at a titre of 1/160 at presentation. CT-scan of frontal sinuses revealed a polypoid mass with bone erosions, and nasal mucosal biopsy revealed granulomatous inflammatory formation without vasculitis. Two weeks after institution of iv CP pulses, the patient experienced acute abdominal pain, mouth ulcers, haemoptysis and dyspnoea. Chest X-ray and CT-scan revealed peribronchial infiltration on the right side with small pericardial effusion. Three pulses of 1 gr iv methylprednisolone were added to his treatment regimen. Over the next few months, the patient had
Case 5 In this 41-year-old man the right tympanic membrane and nasal septum were found to be perforated at presentation. Chest X-rays and CT-scan revealed multiple pulmonary infiltrations with cavities in the left lung. PPD was positive. Nasal mucosal biopsy and OLB revealed granulomatous inflammation and stain for M . tuberculosis and culture were negative. The patient received isoniazid prophylaxis in addition to his treatment regimen.
Discussion The present study is a preliminary pilot investigation to assess the efficacy of intermittent high-dose intravenous cyclophosphamide treatment in WG. The major advantage of ivp-CP treatment is a reduction in long-term drug-related toxicity compared to a low-dose daily regimen [8]. However, the efficacy of ivp-CP in WG compared to that of low-dose daily cyclophophamide is not certain. Two of our patients experienced complete remission with ivp-CP treatment, and they sustained a drug-free remission 24 months after the cessation of treatment. At that time, however, one of these two patients developed features of active disease. Two patients, after an initial remission, experienced recurrence of active features of the disease 4 and 12 months, respectively, after the pulse treatment had stopped. These patients regained remission with oral low-dose CP. In one patient, ivp-CP was totally ineffective, and the patient achieved and sustained improvement on a daily lowdose regimen. These results are in agreement with the findings of two previous studies [13,14] which reported high relapse rates. In contrast, Haubitz et aJ. [15] have reported similar relapse rates in patients treated with ivp-CP and in those treated with a lowdose daily cyclophosphamide (2/8 and 3/15, respectively).
282
A. A. DROSOS et al.
These differences may be explained by the different protocols used in the ivp-CP administration and corticosteroid administration. It is also possible that there is a subset of WG which is responsive to pulse CP treatment. In summary, our results suggest that the ivp-CP treatment may not achieve a high degree of sustained remission in WG. Furthermore, carefully planned clinical trials are needed to define the role of ivp-CP in the treatment of WG patients.
References Fauci AS, Haynes BF. Katz P. The spectrum of vasculitis: clinical, pathologic. immunologic and therapeutic considerations. Ann Intern Med 1978: 89: 660-76. Hollander D. Manning L. The use of alkylating agent in the treatment of Wegener's granulomatosis. Ann Intern Med 1967: 67: 393-8. Fauci AS, Wolfl SM. Wegener's granulomatosis: studies in eighteen patients and a review of the literature. Medicine 1973: 52: 535-61. Keza M J . Dornfeld L. Goldberg LS, Bluestone P. Pearson CM. Wegener's granulomatosis : long-term follow-up of patients treated with cyclophosphamide. Arthritis Rheum 1975: 18: 501-6. Fauci AS. Haynes BF. Katz P. WolK SM. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ariri Interri Med 1 9 8 3 : 98: 76-85.
6 Decker JC. Toxicity of immunosuppressive drugs in man. Arthritis Rheum 1973: 16: 89-91. 7 Schein PS. Wino Kur SH. Immunosuppressive and cytotoxic chemotherapy : long-term complications. Ariri lriterri Med 1 9 7 5 : 82: 84-95. 8 Ballow JF, Austin HA 111. Tsokos GC, Antonovych ' I T , Steinberg HD. Klippel JH. Lupus nephritis. Arin Iritcrri ,tied 1 9 8 7 : 106: 79-94. 9 Bombardieri S. Hughes GRV, Neri R. Del Bravo D. Del Bono I,. Cyclophosphamide in severe polymyositis. Imicet 1989 : 1 : 1138-9. 10 Leroy JP. Drosos AA. Yiannopoulos DI. Youinou 1'. Moutsopoulos HM. Intravenous pulse cyclophosphamide therapy in myositis and Sjogren's syndrome. Arthritis Kheitrri 1990: 3 3 : 1579-81. 11 Fort JG, Abraxo JL. Reversal of progressive necrotiaing vasculitis with intravenous pulse cyclophosphamide and methylprednizone. Arthritis Rheurn 1988 : 31 : 1 194-8. 12 Nolle B, Specks V. Ludemann J, Rohrbach MS, Deremec RA. Gross WL. Anticytoplasmic autoantibodies : their immunodiagnostic value in Wegener's granulomatosis. Ariri lritcrri Med 1 9 8 9 : 111: 2 8 4 0 . 1 3 Hoffman GS. Leavitt RY, Fleisher TA. Minor JR, Fauci AS. Treatment of Wegener's granulomatosis with intermittent high-dose intravenous cyclophosphamide. Arri 1 Mrd 1 9 9 0 : 89: 403-10. 14 Ulmer M. Reinhold-Keller E. Gross WL. Alternative treatment strategies in Wegener's granulomatosis: first results of a prospective study. APMIS 1 9 9 0 : 98 (Suppl. 19): 5 1 . 15 Haubitz M. Frei U. Rother U. Brunkhorst R. Koch KM. Cyclophosphamide pulse therapy in Wegener's granulomatosis. Nephrol Dial Transplant 1991 ; 6: 531-5.
Received 22 November 1991. accepted 27 January 1992.
Correspondence: A. A. Crosos. MD. Department of Internal Medicine, University of Ioannina. 451 1 0 Ioannina. Greece.
