Cyclophosphamide-Induced Remissions in Advanced Polyarteritis Nodosa
ANTHONY S. FAUCI, MD JOHN L DOPPMAN, SHELDON M
MD
WOLFF, MD.
Bethesda, Maryland
Two patients with far advanced polyarteritis nodosa involving multiple organ systems and with extensive aneurysm formation demonstrable by celiac axis and renal arterlograms were treated with oral cyclophosphamide, 1 to 2 mg/kg/day, and alternate day prednisone therapy. Dramatic remissions of disease activity were achieved within weeks of initiation of therapy. Repeat angiograms obtained after one year revealed complete resolution of all aneurysms. Both patients are now receiving only cyclophosphamide and are maintained in complete remission 27 and 18 months after the start of therapy. Cyclophosphamide therapy can thus be highly effective even in far advanced polyarteritis nodosa. Polyarteritis nodosa is a disease characterized by recurrent progressive necrotizing vasculitis of small and medium-sized muscular arteries [ 11. It involves multiple organ systems and has protean clinical manifestations with a high incidence of fever, renal disease, hypertension, mononeuritis multiplex and severe visceral involvement with aneurysmal dilatation of small and medium-sized arteries at the sites of involvement [ 1,2]. The prognosis of polyarteritis nodosa is quite grave despite treatment with corticosteroids. The role of cytotoxic therapy in the disease has not been adequately evaluated and is unclear at present. Because of the dramatic therapeutic remissions we have consistently achieved using cyclophosphamide in Wegener’s granulomatosis, a distinct entity with similarities to polyarteritis nodosa [s], we have now begun treating polyarteritis nodosa patients with cyclophosphamide. In this report we describe dramatic complete clinical remissions including disappearance of angiographically demonstrated multiple aneurysms in two patients with advanced corticosteroid-resistant polyarteritis nodosa who were treated with cyclophosphamide CASE REPORTS
Case 1. This 26 year old man had a history of seasonal asthma since age two years. In 1969, at age 18, his asthmatic symptoms became much more From the Laboratory of Clinical Investigatron, National lnsbtute of Allergy and lnfectrous Diseases and the Diagnostic Radiology Department, The Clinical Center, Nabonal Institutes of Health, Bethesda, Maryland. Requests for reprints should be addressed to Dr Anthony S Faucl, Laboratory of Clinrcal Investigation, Nabonal Institute of Allergy and Infectious Diseases, Building 10, Room 11813, National Institutes of Health, Bethesda, Maryland 20014 Manuscript accepted November 14, 1977.
890
May 1978
severe resulting in several hospitalizations and finally requiring daily corticosteroid therapy. From 1970 to 1972 he was desensitized to various environmental allergens In September 1972 an urticarial rash on both hands developed together with an exacerbation of hrs asthmatic symptoms All these symptoms responded to an increase in hts corticosteroid dosage However, within two weeks a right foot drop developed followed by progressive painful dysesthesias and paresis of both legs. This was accompanied by pulmonary infiltrates, severe asthmatic symptoms and peripheral eosinophilia Increase in hts corticosteroid dosage resulted in resolution of his pulmonary infiltrates and asthmatic symptoms together with stabilization of his mononeurttis multiplex leaving a residual right foot drop
The American Journal of Medicine
Volume 84
CYCLOPHOSPHAMIDEINDUCED REMISSION IN POLYARTERITIS NODOSA-FAUCI
In February 1973 he experienced severe compression fractures of several lumbar vertebrae secondary to corticosteroid-induced osteoporosis. Over the next two years he had several episodes of pulmonary infiltrates, asthmatic symptoms and eosinophilla. These again responded to an increase in corticosteroid dosage. However in June 1975 his mononeurltis multiplex progressed despite the administration of 12 mg of betamethasone a day. He was referred and admltted to the National Institutes of Health (NIH) in June 1975. Following admission to NIH his condition continued to deteriorate rapidly. The mononeuritis multiplex became much worse with bilateral distal lower extremity paresis rendering him completely unable to walk, as well as left median and right radial, median and ulnar nerve paresis and left peripheral facial nerve palsy. He had grand mal seizures, but spinal fluid examination was negative. Pulmonary infiltrates worsened and hypertension developed for which multiple antihypertensive drugs were needed for control. His erythrocyte sedimentation rate increased to 108 mm/hour. His hepatitis-associated antigen (HAA) was negative as were antinuclear antibody (ANA) titers. Bilateral renal and celiac axis arteriograms revealed multiple small (1 to 4 mm) aneurysms in both kidneys together with areas suggestive of small infarcts. The hepatic vasculature was most
ET AL.
extraordinary with many aneurysms (3 to 7 mm)‘scattered throughout (Figure 1A and lB), and focal strictures and obstructions of lntrahepatic arteries. Cyclophosphamide therapy, 2 mg/kg/day orally, was started and prednisone was substituted for betamethasone with the intention of converting to an alternate day regimen. Within three weeks there was a marked diminution of his mononeuritis multiplex and disappearance of his facial nerve palsy. His pulmonary infiltrates cleared, he had no more seizures, his hypertension was well controlled, he was able to walk and his feeling of well being markedly improved. Within six weeks therapy was converted to 80 mg of prednisone on alternate days, and the dose of cyclophosphamide was stabilized at 125 mg/day upon his discharge in September 1975. He was followed closely as an outpatient and readmitted for routine evaluation every three to four months. At his first readmission in February 1978 his erythrocyte sedimentation rate was 10 mm/hour, he was normotensive without antihypertensive medications and he was asymptomatic apart from some residual hand weakness and foot drop that was lessening with physical therapy. One year after the institution of cyclophosphamide therapy (July 1975) renal and celiac axis arteriograms were repeated. The studies showed complete resolution of the severe renal
Figure 1. Selective celiac arteriogram demonstrates large hepatic arteries (A) and multiple aneurysms (A and B) throughout the liver. One year after therapy (C), the hepatic arteries are smaller and all aneurysms have disappeared.
1978
The American Journal of Medlclne
Volume 64
891
CYCLOPHOSPHAMIDE
INDUCED REMISSION
IN POLYARTERITIS
NODOSA-FAUCI
ET AL.
Figure 2. Selective left renal arteriogram demonstrates multiple intrarenal aneurysms (arrows) in arterial (A) and capillary (B) phase. Note cortical defects in lower pole (arrows) probably due to infarcts. One year after therapy (C) the aneurysms have disappeared, and the cortex of the lower pole is minimally scarred.
and hepatic artery involvement (Figure 1C). He continued to do extremely well. In May 1977 his alternate day prednisone dose, which had been gradually tapered, was discontinued. His cyclophosphamide dose has been reduced to 75 mg/day with a plan to continue gradual tapering. At present he is employed and completely well with only residual peripheral neurologic impairment. Case 2. This 52 year old man was well until late 1973 when he experienced wheezing and cough for the first time; it progressed in severity over the next two years and forced his early retirement in 1975. Chest film revealed calcified hilar nodes and apical scarring. In February 1976 he had the onset of myalgias and weakness involving the calf and thigh muscles together with weight loss. He was seen by his local
692
May 1976
The American Journal of Medicine
Volume 64
physician who instituted prednisone therapy, 5 mg four times a day. This relieved his respiratory symptoms but not his myalgias. Subsequently fever developed (with temperatures to 102’F) and anorexia; he was found to have an erythrocyte sedimentation rate of 45 mm/hour. Biopsy of his painful left gastrocnemius muscle revealed necrotizing small vessel vasculitis. His prednisone dose was increased to 120 mg/day with some resolution of his myalgias. However, his condition continued to deteriorate with the onset of testicular pain as well as progressive parasthesias and severe weakness in the area of the right ulnar and left median nerve distributions, and in both feet. Weight loss continued and totaled 40 pounds. In addition, insulin-requiring diabetes mellitus developed during the high dose prednisone regimen.
CYCLDf’HDSF’HAMlDEINDUCED REMISSON IN !‘CLYARTERlTlS NDDDSA-FAUCI
Because of his deteriorating condition (despite high dose prednisone therapy) the patient was admitted to the NIH Clinical Center in April 1976. During the first 10 days of his admission, while still receiving 120 mg prednisone/day, his disease rapidly progressed. the mononeuritis multiplex in his arms and legs became much more severe with extreme weakness of grip, especially in his right hand, and more severe paresthesias and burning sensation in both hands and feet. His erythrocyte sedimentation rate increased from 52 to 109 mm/hour (Westergren method) and a 15 per cent eosinophilia developed with a white blood cell count of 12,000/mm3. His blood pressure rose to 200/130 mm Hg and his creatinine clearance was 30 cc/min. Rheumatoid factor was positive in a titer of 1:4096; lupus erythematosus preparation, ANA titer and HAA were negative. Nodular skin lesions developed which, on biopsy, revealed necrotizing vasculitis. Renal and celiac axis arteriograms revealed multiple 2 to 5 mm aneuryms in both kidneys (Figure 2A and B), liver, spleen and pancreatic arteries. The renal cortices distal to the aneurysms revealed wedge-shaped areas of nonperfusion suggestive of infarcts. The administration of cyclophosphamide, 2 mg/kg/day orally, was started (May 1976). At this point his prednisone regimen (120 mg/day) was gradually tapered with the aim of converting to an alternate day schedule. Within 10 days of the institution of cyclophosphamide therapy the patient manifested signs of subjective and objective improvement which continued dramatically over the following six weeks. His mononeuritis multiplex greatly diminished and he rapidly regained strength and range of motion in his hands. His hypertension resolved and his creatinine clearance increased to 98 cc/min. Within 19 days of beginning cyclophosphamide therapy, his prednisone regimen was converted to 80 mg on alternate days with further tapering planned. He was discharged in June 1976 receiving cyclophosphamide, 100 mgiday, and prednisone, 60 mg/day, with tapering. He was readmitted in three months doing extremely well. His neuropathy continued to diminish. He was normotensive; his erythrocyte sedimentation rate was 14 mm/hour; his rheumatoid factor was negative and his creatinine clearance was 120 cc/min. He regained his 40 pound weight loss. He was followed with admission at three month intervals and continued to do well. One year after the initiation of cyclophosphamide therapy the renal (Figure 2C) and celiac axis ark&grams were repeated and showed complete resolution of all aneurysms. At present, 18 months after the institution of cyclophosphamide therapy, he is completely well except for some mild residual parasthesias and weakness in his hands as well as some mild wheezing easily controlled with aminophylline. The administration of prednisone has been discontinued completely, and he is receiving only cyclophosphamide, 75 mglday. COMMENTS In the present cases the patients illustrate remarkable therapeutic responses to cyclophosphamide therapy
in a clinical setting in which far advanced polyarteritis nodosa was rapidly progressing despite high dose corticosteroid therapy. In addition to the induction and
ET AL.
maintenance of complete clinical remission, striking reversal of severe aneurysmal involvement of abdominal vasculature as demonstrated by normalization of angiographic findings was noted. Prior to the use of cot-ticosteroids in polyarteritis nodosa the disease was almost inevitably progressive leading finally to death [4]. With the use of corticosteroid therapy in this disease, the prognosis has improved somewhat from an over-all five year survival of 13 per cent in untreated patients to 48 per cent in corticosteroid-treated patients [4,5]. The prognosis was even worse in those patients who presented with hypertension or renal disease. Recently, isolated reports have suggested favorable clinical responses in polyarteritis nodosa to cytotoxic therapy [6-g]. One of the difficulties in establishing therapeutic guidelines in polyarteritis nodosa has been the uncommonness of this disease as well its frequent confusion with other necrotizing vasculitides, such as hypersensitivity diseases characterized by small vessel vasculitis with or without granuloma formation [ 1,2, lo]. It has been suggested that the presence of multiple aneurysms in small and medium-sized arteries demonstrable by angiography is pathognomic of polyarteritis nodosa [ 11,121. Our patients not only had the striking characteristic changes on abdominal angiography which together with their classic clinical picture firmly established the diagnosis of polyarteritis nodosa, but each also demonstrated dramatic disappearance of abnormal angiographic findings after one year of cyclophosphamide therapy. It has been suggested that regression of aneurysms in polyarteritis nodosa may be secondary to sclerosis rather than to a return to normal of vessel walls [ 131 and that it may be unrelated to treatment or clinical course [ 141. However, it seems clear in the present cases that as aneurysms disappeared, not only did vessels appear normal on restudy but also the remission as seen on angiography was accompanied by a complete clinical remission lasting 26 months and 15 months at the time of this writing. Moreover, both patients fell into the highest risk category with hypertension and/or renal disease, and their condition was progressively deteriorating during corticosteroid therapy when cyclophosphamide therapy was initiated. With low dose (1 to 2 mg/kg/day) cyclophosphamide therapy in Wegener’s granulomatosis [ 51, we have been able to induce remissions in over 95 per cent of our more than 40 patients. It seems clear that equally as favorable responses may well be obtained with cyclophosphamide therapy in polyarteritis nodosa, and it is likely that early initiation of cyclophosphamide therapy in this disease may dramatically improve its historically grave prognosis.
May 1979
The American Journal of Medicine
Volume 64
693
CYCLOPHOSPHAMIDEINDUCED REMISSION IN POLYARTERITIS NODOSA-FAUCI
ET AL.
REFERENCES 1. 2. 3 4. 5
6
7.
6.
894
Zeek PM: Periarteritis nodosa and other forms of necrotizing angiitis. N Engl J Med 248: 764, 1953. Rose GA, Spencer H: Polyarteritis nodosa. Cl J Med 26 43, 1957. Rupe CE: Treatment of polyarteritrs nodosa and related arteritities Mod Treat 3: 1260, 1966 Frohnert PP, Sheps SG: Long-term follow-up study of periarteritis nodosa. Am J Med 43: 6, 1967 Fauci AS, Wolff SM: Wegener’s granulomatosrs: studies In eighteen patients and review of the literature Medicine (Baltimore) 52: 535, 1973 Melam H, Patterson R: Periarteritis nodosa. A remission achieved with combined prednisone and azathioprine therapy Am J Dis Child 121: 424, 1971. Tuma S, Chaimovitz C, Szylman P, et al : Periarteritis nodosa in the kidney Recovery following immunosuppressive therapy. JAMA 235: 260, 1976. Glanz S, Bittner SJ, Berman MA, et al.: Regression of coro-
May 1978
The American Journal of Medicine
Volume 84
9 10
11.
12. 13
14.
nary-artery aneurysms in infantile polyarteritis nodosa. N Engl J Med 294: 939, 1976 R&mold EW, Weinberg AG, Fink CW, et al.. Polyarterrtrs In children Am J Dis Child 130: 534, 1976 Afarcon-Segovia D: The necrotizing vasculitides: A new pathogenetic classification. Med Clin North Am 61. 241, 1977 Bron KM, Strott CA, Shapiro AP: The diagnostic value of antiographic observations in polyarteritis nodosa Arch Intern Med 116 450. 1965. Dornfeld L, Lecky JW, Peter JB Polyarteritis and intrarenal renal artery aneurysms JAMA 215 1950, 1971 Kato H, Kocke S, Yamamoto M, et al.. Coronary artery aneurysms in infants and young children with acute febrile muco-cutaneous lymph node syndrome J Pediatr 66: 692, 1975 Robins JM, Bookstern JJ: Regressing aneurysms in periarterrtrs nodosa Radiology 104. 36, 1972
ANTHONY S. FAUCI, MD JOHN L DOPPMAN, SHELDON M
MD
WOLFF, MD.
Bethesda, Maryland
Two patients with far advanced polyarteritis nodosa involving multiple organ systems and with extensive aneurysm formation demonstrable by celiac axis and renal arterlograms were treated with oral cyclophosphamide, 1 to 2 mg/kg/day, and alternate day prednisone therapy. Dramatic remissions of disease activity were achieved within weeks of initiation of therapy. Repeat angiograms obtained after one year revealed complete resolution of all aneurysms. Both patients are now receiving only cyclophosphamide and are maintained in complete remission 27 and 18 months after the start of therapy. Cyclophosphamide therapy can thus be highly effective even in far advanced polyarteritis nodosa. Polyarteritis nodosa is a disease characterized by recurrent progressive necrotizing vasculitis of small and medium-sized muscular arteries [ 11. It involves multiple organ systems and has protean clinical manifestations with a high incidence of fever, renal disease, hypertension, mononeuritis multiplex and severe visceral involvement with aneurysmal dilatation of small and medium-sized arteries at the sites of involvement [ 1,2]. The prognosis of polyarteritis nodosa is quite grave despite treatment with corticosteroids. The role of cytotoxic therapy in the disease has not been adequately evaluated and is unclear at present. Because of the dramatic therapeutic remissions we have consistently achieved using cyclophosphamide in Wegener’s granulomatosis, a distinct entity with similarities to polyarteritis nodosa [s], we have now begun treating polyarteritis nodosa patients with cyclophosphamide. In this report we describe dramatic complete clinical remissions including disappearance of angiographically demonstrated multiple aneurysms in two patients with advanced corticosteroid-resistant polyarteritis nodosa who were treated with cyclophosphamide CASE REPORTS
Case 1. This 26 year old man had a history of seasonal asthma since age two years. In 1969, at age 18, his asthmatic symptoms became much more From the Laboratory of Clinical Investigatron, National lnsbtute of Allergy and lnfectrous Diseases and the Diagnostic Radiology Department, The Clinical Center, Nabonal Institutes of Health, Bethesda, Maryland. Requests for reprints should be addressed to Dr Anthony S Faucl, Laboratory of Clinrcal Investigation, Nabonal Institute of Allergy and Infectious Diseases, Building 10, Room 11813, National Institutes of Health, Bethesda, Maryland 20014 Manuscript accepted November 14, 1977.
890
May 1978
severe resulting in several hospitalizations and finally requiring daily corticosteroid therapy. From 1970 to 1972 he was desensitized to various environmental allergens In September 1972 an urticarial rash on both hands developed together with an exacerbation of hrs asthmatic symptoms All these symptoms responded to an increase in hts corticosteroid dosage However, within two weeks a right foot drop developed followed by progressive painful dysesthesias and paresis of both legs. This was accompanied by pulmonary infiltrates, severe asthmatic symptoms and peripheral eosinophilia Increase in hts corticosteroid dosage resulted in resolution of his pulmonary infiltrates and asthmatic symptoms together with stabilization of his mononeurttis multiplex leaving a residual right foot drop
The American Journal of Medicine
Volume 84
CYCLOPHOSPHAMIDEINDUCED REMISSION IN POLYARTERITIS NODOSA-FAUCI
In February 1973 he experienced severe compression fractures of several lumbar vertebrae secondary to corticosteroid-induced osteoporosis. Over the next two years he had several episodes of pulmonary infiltrates, asthmatic symptoms and eosinophilla. These again responded to an increase in corticosteroid dosage. However in June 1975 his mononeurltis multiplex progressed despite the administration of 12 mg of betamethasone a day. He was referred and admltted to the National Institutes of Health (NIH) in June 1975. Following admission to NIH his condition continued to deteriorate rapidly. The mononeuritis multiplex became much worse with bilateral distal lower extremity paresis rendering him completely unable to walk, as well as left median and right radial, median and ulnar nerve paresis and left peripheral facial nerve palsy. He had grand mal seizures, but spinal fluid examination was negative. Pulmonary infiltrates worsened and hypertension developed for which multiple antihypertensive drugs were needed for control. His erythrocyte sedimentation rate increased to 108 mm/hour. His hepatitis-associated antigen (HAA) was negative as were antinuclear antibody (ANA) titers. Bilateral renal and celiac axis arteriograms revealed multiple small (1 to 4 mm) aneurysms in both kidneys together with areas suggestive of small infarcts. The hepatic vasculature was most
ET AL.
extraordinary with many aneurysms (3 to 7 mm)‘scattered throughout (Figure 1A and lB), and focal strictures and obstructions of lntrahepatic arteries. Cyclophosphamide therapy, 2 mg/kg/day orally, was started and prednisone was substituted for betamethasone with the intention of converting to an alternate day regimen. Within three weeks there was a marked diminution of his mononeuritis multiplex and disappearance of his facial nerve palsy. His pulmonary infiltrates cleared, he had no more seizures, his hypertension was well controlled, he was able to walk and his feeling of well being markedly improved. Within six weeks therapy was converted to 80 mg of prednisone on alternate days, and the dose of cyclophosphamide was stabilized at 125 mg/day upon his discharge in September 1975. He was followed closely as an outpatient and readmitted for routine evaluation every three to four months. At his first readmission in February 1978 his erythrocyte sedimentation rate was 10 mm/hour, he was normotensive without antihypertensive medications and he was asymptomatic apart from some residual hand weakness and foot drop that was lessening with physical therapy. One year after the institution of cyclophosphamide therapy (July 1975) renal and celiac axis arteriograms were repeated. The studies showed complete resolution of the severe renal
Figure 1. Selective celiac arteriogram demonstrates large hepatic arteries (A) and multiple aneurysms (A and B) throughout the liver. One year after therapy (C), the hepatic arteries are smaller and all aneurysms have disappeared.
1978
The American Journal of Medlclne
Volume 64
891
CYCLOPHOSPHAMIDE
INDUCED REMISSION
IN POLYARTERITIS
NODOSA-FAUCI
ET AL.
Figure 2. Selective left renal arteriogram demonstrates multiple intrarenal aneurysms (arrows) in arterial (A) and capillary (B) phase. Note cortical defects in lower pole (arrows) probably due to infarcts. One year after therapy (C) the aneurysms have disappeared, and the cortex of the lower pole is minimally scarred.
and hepatic artery involvement (Figure 1C). He continued to do extremely well. In May 1977 his alternate day prednisone dose, which had been gradually tapered, was discontinued. His cyclophosphamide dose has been reduced to 75 mg/day with a plan to continue gradual tapering. At present he is employed and completely well with only residual peripheral neurologic impairment. Case 2. This 52 year old man was well until late 1973 when he experienced wheezing and cough for the first time; it progressed in severity over the next two years and forced his early retirement in 1975. Chest film revealed calcified hilar nodes and apical scarring. In February 1976 he had the onset of myalgias and weakness involving the calf and thigh muscles together with weight loss. He was seen by his local
692
May 1976
The American Journal of Medicine
Volume 64
physician who instituted prednisone therapy, 5 mg four times a day. This relieved his respiratory symptoms but not his myalgias. Subsequently fever developed (with temperatures to 102’F) and anorexia; he was found to have an erythrocyte sedimentation rate of 45 mm/hour. Biopsy of his painful left gastrocnemius muscle revealed necrotizing small vessel vasculitis. His prednisone dose was increased to 120 mg/day with some resolution of his myalgias. However, his condition continued to deteriorate with the onset of testicular pain as well as progressive parasthesias and severe weakness in the area of the right ulnar and left median nerve distributions, and in both feet. Weight loss continued and totaled 40 pounds. In addition, insulin-requiring diabetes mellitus developed during the high dose prednisone regimen.
CYCLDf’HDSF’HAMlDEINDUCED REMISSON IN !‘CLYARTERlTlS NDDDSA-FAUCI
Because of his deteriorating condition (despite high dose prednisone therapy) the patient was admitted to the NIH Clinical Center in April 1976. During the first 10 days of his admission, while still receiving 120 mg prednisone/day, his disease rapidly progressed. the mononeuritis multiplex in his arms and legs became much more severe with extreme weakness of grip, especially in his right hand, and more severe paresthesias and burning sensation in both hands and feet. His erythrocyte sedimentation rate increased from 52 to 109 mm/hour (Westergren method) and a 15 per cent eosinophilia developed with a white blood cell count of 12,000/mm3. His blood pressure rose to 200/130 mm Hg and his creatinine clearance was 30 cc/min. Rheumatoid factor was positive in a titer of 1:4096; lupus erythematosus preparation, ANA titer and HAA were negative. Nodular skin lesions developed which, on biopsy, revealed necrotizing vasculitis. Renal and celiac axis arteriograms revealed multiple 2 to 5 mm aneuryms in both kidneys (Figure 2A and B), liver, spleen and pancreatic arteries. The renal cortices distal to the aneurysms revealed wedge-shaped areas of nonperfusion suggestive of infarcts. The administration of cyclophosphamide, 2 mg/kg/day orally, was started (May 1976). At this point his prednisone regimen (120 mg/day) was gradually tapered with the aim of converting to an alternate day schedule. Within 10 days of the institution of cyclophosphamide therapy the patient manifested signs of subjective and objective improvement which continued dramatically over the following six weeks. His mononeuritis multiplex greatly diminished and he rapidly regained strength and range of motion in his hands. His hypertension resolved and his creatinine clearance increased to 98 cc/min. Within 19 days of beginning cyclophosphamide therapy, his prednisone regimen was converted to 80 mg on alternate days with further tapering planned. He was discharged in June 1976 receiving cyclophosphamide, 100 mgiday, and prednisone, 60 mg/day, with tapering. He was readmitted in three months doing extremely well. His neuropathy continued to diminish. He was normotensive; his erythrocyte sedimentation rate was 14 mm/hour; his rheumatoid factor was negative and his creatinine clearance was 120 cc/min. He regained his 40 pound weight loss. He was followed with admission at three month intervals and continued to do well. One year after the initiation of cyclophosphamide therapy the renal (Figure 2C) and celiac axis ark&grams were repeated and showed complete resolution of all aneurysms. At present, 18 months after the institution of cyclophosphamide therapy, he is completely well except for some mild residual parasthesias and weakness in his hands as well as some mild wheezing easily controlled with aminophylline. The administration of prednisone has been discontinued completely, and he is receiving only cyclophosphamide, 75 mglday. COMMENTS In the present cases the patients illustrate remarkable therapeutic responses to cyclophosphamide therapy
in a clinical setting in which far advanced polyarteritis nodosa was rapidly progressing despite high dose corticosteroid therapy. In addition to the induction and
ET AL.
maintenance of complete clinical remission, striking reversal of severe aneurysmal involvement of abdominal vasculature as demonstrated by normalization of angiographic findings was noted. Prior to the use of cot-ticosteroids in polyarteritis nodosa the disease was almost inevitably progressive leading finally to death [4]. With the use of corticosteroid therapy in this disease, the prognosis has improved somewhat from an over-all five year survival of 13 per cent in untreated patients to 48 per cent in corticosteroid-treated patients [4,5]. The prognosis was even worse in those patients who presented with hypertension or renal disease. Recently, isolated reports have suggested favorable clinical responses in polyarteritis nodosa to cytotoxic therapy [6-g]. One of the difficulties in establishing therapeutic guidelines in polyarteritis nodosa has been the uncommonness of this disease as well its frequent confusion with other necrotizing vasculitides, such as hypersensitivity diseases characterized by small vessel vasculitis with or without granuloma formation [ 1,2, lo]. It has been suggested that the presence of multiple aneurysms in small and medium-sized arteries demonstrable by angiography is pathognomic of polyarteritis nodosa [ 11,121. Our patients not only had the striking characteristic changes on abdominal angiography which together with their classic clinical picture firmly established the diagnosis of polyarteritis nodosa, but each also demonstrated dramatic disappearance of abnormal angiographic findings after one year of cyclophosphamide therapy. It has been suggested that regression of aneurysms in polyarteritis nodosa may be secondary to sclerosis rather than to a return to normal of vessel walls [ 131 and that it may be unrelated to treatment or clinical course [ 141. However, it seems clear in the present cases that as aneurysms disappeared, not only did vessels appear normal on restudy but also the remission as seen on angiography was accompanied by a complete clinical remission lasting 26 months and 15 months at the time of this writing. Moreover, both patients fell into the highest risk category with hypertension and/or renal disease, and their condition was progressively deteriorating during corticosteroid therapy when cyclophosphamide therapy was initiated. With low dose (1 to 2 mg/kg/day) cyclophosphamide therapy in Wegener’s granulomatosis [ 51, we have been able to induce remissions in over 95 per cent of our more than 40 patients. It seems clear that equally as favorable responses may well be obtained with cyclophosphamide therapy in polyarteritis nodosa, and it is likely that early initiation of cyclophosphamide therapy in this disease may dramatically improve its historically grave prognosis.
May 1979
The American Journal of Medicine
Volume 64
693
CYCLOPHOSPHAMIDEINDUCED REMISSION IN POLYARTERITIS NODOSA-FAUCI
ET AL.
REFERENCES 1. 2. 3 4. 5
6
7.
6.
894
Zeek PM: Periarteritis nodosa and other forms of necrotizing angiitis. N Engl J Med 248: 764, 1953. Rose GA, Spencer H: Polyarteritis nodosa. Cl J Med 26 43, 1957. Rupe CE: Treatment of polyarteritrs nodosa and related arteritities Mod Treat 3: 1260, 1966 Frohnert PP, Sheps SG: Long-term follow-up study of periarteritis nodosa. Am J Med 43: 6, 1967 Fauci AS, Wolff SM: Wegener’s granulomatosrs: studies In eighteen patients and review of the literature Medicine (Baltimore) 52: 535, 1973 Melam H, Patterson R: Periarteritis nodosa. A remission achieved with combined prednisone and azathioprine therapy Am J Dis Child 121: 424, 1971. Tuma S, Chaimovitz C, Szylman P, et al : Periarteritis nodosa in the kidney Recovery following immunosuppressive therapy. JAMA 235: 260, 1976. Glanz S, Bittner SJ, Berman MA, et al.: Regression of coro-
May 1978
The American Journal of Medicine
Volume 84
9 10
11.
12. 13
14.
nary-artery aneurysms in infantile polyarteritis nodosa. N Engl J Med 294: 939, 1976 R&mold EW, Weinberg AG, Fink CW, et al.. Polyarterrtrs In children Am J Dis Child 130: 534, 1976 Afarcon-Segovia D: The necrotizing vasculitides: A new pathogenetic classification. Med Clin North Am 61. 241, 1977 Bron KM, Strott CA, Shapiro AP: The diagnostic value of antiographic observations in polyarteritis nodosa Arch Intern Med 116 450. 1965. Dornfeld L, Lecky JW, Peter JB Polyarteritis and intrarenal renal artery aneurysms JAMA 215 1950, 1971 Kato H, Kocke S, Yamamoto M, et al.. Coronary artery aneurysms in infants and young children with acute febrile muco-cutaneous lymph node syndrome J Pediatr 66: 692, 1975 Robins JM, Bookstern JJ: Regressing aneurysms in periarterrtrs nodosa Radiology 104. 36, 1972
