as
rt
De Novo Systemic Vasculitis in a Renal Transplant Recipient
ROBERT W. SCHRINER, M.D., Division of Thoracic Diseases and Internal Medicine; AARON K. NADA, M.D.,* Division of Nephrology and Internal Medicine; J. T. LIE, M.D., Division of Pathology; MARK P. WILHELM, M.D., Division ofInfectious Diseases and Internal Medicine; SYLVESTER STERIOFF, M.D., Section of Transplantation Surgery; JAMES V. DONADIO, Jr., M.D., Division ofNephrology and Internal Medicine
Abdominal pain, oligoarthritis, macular skin rash, and urine sediment with more than 100 erythrocytes per high-power field and proteinuria developed in a renal transplant recipient who had no prior history of an underlying connective tissue disease. A polyarteritis-type necrotizing vasculitis was detected in the small bowel mesentery. A search for other etiologic factors revealed none. This case demonstrates that de novo vasculitis can develop in renal transplant recipients despite adequate immunosuppressive regimens and may respond to increased dosages of corticosteroids.
Vasculitis has been reported to develop and progress in transplant recipients receiving immunosuppressive therapy.l" In most cases, this condition has occurred in the setting of a recurrent autoimmune vasculitic process-s or an infection. 6-8 We found one previous case report ofa de novo angiitis ofthe central nervous system in a renal transplant recipient who was receiving prednisone and azathioprine." Herein we describe a patient in whom evidence of a systemic vasculitis developed 2 years after he had received a cadaveric renal allograft and while he was taking a triple-drug immunosuppressive regimen. *Current address: John A. Burns School of Medicine, Honolulu, Hawaii. Address reprint requests to Dr. R. W. Schriner, Division of Thoracic Diseases, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 66:183-186, 1991
REPORT OF CASE A 52-year-old man had received a renal allograft in 1987 because of end-stage autosomal dominant polycystic kidney disease. Stable allograft function was maintained with immunosuppressive therapy that consisted of cyclosporine (200 mg twice a day, with whole blood trough levels of 85 and 74 ng/ml; high-performance liquid chromatographic method with a therapeutic range of 100 to 300 ng/ml), azathioprine (150 mg/day), and prednisone (15 mg/day). He was also taking prazosin hydrochloride, furosemide, minoxidil, and atenolol for hypertension. In April 1989, the patient had undergone a left tibial-talar arthrodesis with external fixation because of degenerative joint disease. Routine follow-up 4 weeks later showed that the allograft function was stable (serum creatinine, 1.7 mg/ dl; no microhematuria or proteinuria on urinalysis). During the next 2 days, he noted the
183
184
VASCULITIS IN RENAL TRANSPLANT RECIPIENT
gradual onset of diffuse abdominal pain associated with emesis and melena. The patient was admitted to a local hospital, where a nasogastric aspirate and stool specimens were guaiac positive. An abdominal roentgenogram and computed tomographic scan were unremarkable except for cysts in the liver and native kidney. Cultures of blood and urine specimens for bacteria were negative. The patient was treated with ranitidine hydrochloride, blood transfusion, and cefoxitin sodium. During the next 24 hours, development of a macular rash on the upper torso, paroxysms of abdominal pain, arthralgias and oligoarthritis in the right upper extremity, and hematuria prompted transfer of the patient to our institution. At the time of admission, the physical examination disclosed a row-grade fever (temperature of38.2°C), macular rash without purpura on the upper torso, synovitis of the right elbow, abdominal pain in the left upper quadrant distinct from the left native polycystic kidney, and guaiacpositive stools. The transplanted kidney was nontender to palpation. The left ankle was in an external fixation device, but it was not erythematous or swollen. The findings on neurologic examination were normal. The initial laboratory evaluation revealed a urine sediment that contained more than 100 erythrocytes per high-power field and 1+ proteinuria, an erythrocyte sedimentation rate of 31 mm in 1 hour, and a stable serum creatinine concentration of 1.6 mg/dl. Results of liver function tests (aspartate aminotransferase, 15 U/liter; alkaline phosphatase, 90 U/liter; and bilirubin, 1.1 mg/dl) were normal, as was the serum amylase value (65 U/liter). The hemoglobin concentration was 12.7 g/dl, and the leukocyte count was 9.0 x 103/mm3 • Cultures of blood, urine, and aspirate from the right elbow for bacteria, fungi, and viruses were negative. Analysis of synovial fluid from the right elbow showed a total leukocyte count of 2,704/mm 3 , glucose of 142 mg/dl, and no crystals. An echocardiogram demonstrated no valvular vegetations. Stool examination was negative for bacterial pathogens, and no parasites were seen. Antibodies to Histoplasma capsulatum, Blasto-
Mayo Clin Proc, February 1991, Vol 66
myces dermatitidis, Coccidioides immitis, and human immunodeficiency virus type 1 were not detected. Testing for cryptococcal antigen and IgM antibodies to cytomegalovirus was negative. Subsequent urinalysis showed more than 100 erythrocytes per high-power field, occasional erythrocyte casts, and 2+ proteinuria. Tests for hepatitis B surface antigen, anti-neutrophil cytoplasmic antibodies, antinuclear antibodies, myoglobin, and cryoglobulins were negative. Total complement (81 U; normal, 25 to 110) was normal, but the C3 component was slightly reduced (55 mg/dl; normal, 70 to 150). A chest roentgenogram was unremarkable, but abdominal plain films and a computed tomographic scan showed a dilated and thickwalled loop of small bowel. A barium examination of the small bowel disclosed an 8- to 10-cm proximal jejunal segment that had diffusely thickened folds and was nondistensible. A biopsy specimen obtained on extended esophagogastroduodenoscopy showed an inflammatory ulcer with reactive immunoblastic proliferation. Because of persistent symptoms, a laparotomy was performed; four areas of extensive ulceration involved the proximal jejunum as a result of necrotizing vasculitis of the classic polyarteritis type with fibrinoid necrosis (Fig. 1). Although Candida albicans was recovered in culture, no histopathologic evidence of tissue invasion was found. Cytomegalovirus infection was specifically excluded by tissue immunostaining, culture, and the absence of inclusion bodies. The patient had an uneventful recovery from the surgical procedure. Postoperatively, an increase in the dosage of prednisone from 15 to 60 mg/day resulted in clinical and laboratory improvement. He had no further fevers, abdominal pain, rashes, or joint symptoms. At dismissal, the erythrocyte sedimentation rate had decreased to 7 mm in 1 hour, the urinalysis showed 4 to 10 erythrocytes per high-power field but no proteinuria or erythrocyte casts, and the serum creatinine level was 1.7 mg/dl. The hemoglobin concentration was stable (11 g/dl) postoperatively. During the subsequent 6 months, the patient had a stable clinical course. The dosage of pred-
Mayo Clin Proc, February 1991, Vol 66
Fig. 1. Photomicrograph of a representative polyarteritistype necrotizing vasculitis in the small bowel mesentery of a renal transplant recipient with no underlying connective tissue disease. (Hematoxylin-eosin; x160.)
nisone was gradually decreased to 15 mg/day, and the azathioprine and cyclosporine regimens were maintained.
DISCUSSION Polyarteritis nodosa is a multisystem disorder characterized by a pleomorphic cellular infiltration and fibrinoid necrosis of small and mediumsized arteries.P-" The pathogenesis is unknown, but postulated mechanisms include arterial deposition of soluble immune complexes or cellmediated immune processes. The widespread distribution of the arterial lesions in polyarteritis nodosa produces diverse clinical manifestations. In autopsy series, involvement is noted in the kidneys and heart in
VASCULITIS IN RENAL TRANSPLANT RECIPIENT
185
about 70% of cases; in the liver, gastrointestinal tract, and peripheral nerves in 50%; in the mesentery and skeletal muscle in approximately 20%; and in the skin in 5 to 50%.10,11 Laboratory findings are nonspecific but usually include an increased erythrocyte sedimentation rate, anemia, leukocytosis, and abnormal urine sediment when renal involvement is present. Serum cryoglobulins, rheumatoid factor, hepatitis B antigenemia, and diminished concentrations of serum whole complement are observed in 10 to 25% of patients. 11 Conditions that simulate necrotizing vasculitis clinically include left atrial myxoma, infective endocarditis, septicemia, Lyme disease, lymphoma, cholesterol embolization from a largeartery aneurysm, and drug hypersensitivity.l" In the immunocompromised host, cytomegalovirus infection and disseminated cryptococcosis must also be considered in the differential diagnosis.v" These conditions were specifically excluded in the current case. In the polyarteritis nodosa group of systemic vasculitis, corticosteroids are the mainstay of therapy, but a few retrospective studies have shown improved survival with the addition of cyclophosphamide or azathioprine.Pv" The published literature has a paucity of information about the treatment of an autoimmune vasculitic process in a patient already receiving an immunosuppressive regimen. Steinman and associates' reported a dramatic response in a renal transplant recipient with recurrent Wegener's granulomatosis who was treated with an increase in dosage of prednisone from 10 to 40 mg/day and a switch from azathioprine, 150 mgt day, to cyclophosphamide, 150 mg/day. A similar case of recurrent Wegener's granulomatosis seemed to respond to the replacement of azathioprine by cyclophosphamide. 3 In another patient with recurrent Wegener's granulomatosis, however, renal allograft function did not improve by a change from azathioprine to cyclophosphamide, but the duration of treatment' with cyclophosphamide was limited because of a complicating Listeria meningitis." Rothenberg" described a poor response of central nervous system angiitis in a renal transplant recipient to
186
VASCULITIS IN RENAL TRANSPLANT RECIPIENT
treatment that included increasing the dosage of prednisone from 15 to 60 mg/day and substituting cyclophosphamide for azathioprine. Because our patient was doing well after laparotomy and augmentation of his corticosteroid therapy, we elected to continue administering high-dose prednisone for at least 1 month followed by a gradual taper of the dose. This strategy was successful in achieving a quiescent stage.
CONCLUSION An immunologically mediated disease process developed in a renal transplant recipient without an underlying connective tissue disease while he was receiving effective transplant immunosuppressive therapy. This case illustrates that recurrent or de novo vasculitis cannot be excluded in the differential diagnosis of conditions that occur in transplant recipients. In such patients with evidence of vasculitis, an accurate diagnosis is necessary because further management involves increasing the dosage of corticosteroids and perhaps changing cytotoxic agentsfor example, from azathioprine to cyclophosphamide-if a clinical response is not obtained with corticosteroid treatment. REFERENCES 1. Steinman TI, Jaffe BF, Monaco AP, WolffSM, Fauci AS: Recurrence of Wegener's granulomatosis after kidney transplantation: successful re-induction of remission with cyclophosphamide. Am J Med 68:458460, 1980 2. Duvall AJ III, Nelms CR, Williams HL: Necrotizing granuloma of the midline tissues following renal
Mayo Clin Proc, February 1991, Vol 66
3. 4.
5. 6.
7.
8.
9. 10. 11.
12.
13. 14.
transplantation. Trans Am Acad Ophthalmol Otolaryngol 73:1187-1207,1969 Salaman R, Coles GA, Saltissi D: Haemodialysis and transplantation in Wegener's granulomatosis (letter to the editor). Br Med J 280:254, 1980 Curtis JJ, Diethelm AG, Herrera GA, Crowell WT, Whelchel JD: Recurrence of Wegener's granulomatosis in a cadaver renal allograft. Transplantation 36:452-454, 1983 Rothenberg RJ: Isolated angiitis of the brain: case in a renal transplant recipient. Am J Med 79:629-632, 1985 Shrader SK, Watts JC, Dancik JA, Band JD: Disseminated cryptococcosis presenting as cellulitis with necrotizing vasculitis. J Clin Microbiol 24:860-862, 1986 Minars N, Silverman JF, Escobar MR, Martinez AJ: Fatal cytomegalic inclusion disease: associated skin manifestations in a renal transplant patient. Arch Dermatol 113:1569-1571, 1977 Foucar E, Mukai K, Foucar K, Sutherland DER, Van Buren CT: Colon ulceration in lethal cytomegalovirus infection. Am J Clin Pathol 76:788-801, 1981 Zeek PM: Periarteritis nodosa and other forms of necrotizing angiitis. N Engl J Med 248:764-772, 1953 Lie JT: Systemic and isolated vasculitis: a rational approach to classification and pathologic diagnosis. Pathol Annu 24 (Part 1):25-114, 1989 Cohen RD, Conn DL, Ilstrup DM: Clinical features, prognosis, and response to treatment in polyarteritis. Mayo Clin Proc 55:146-155,1980 Conn DL, Hunder GG: Vasculitis and related disorders. In Textbook of Rheumatology. Third edition. Edited by WN Kelley, ED Harris Jr, S Ruddy, CB Sledge. Philadelphia, WB Saunders Company, 1989, pp 1167-1199 Fauci AS, Katz P, Haynes BF, Wolff SM: Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med 301:235-238, 1979 Leib ES, Restivo C, Paulus HE: Immunosuppressive and corticosteroid therapy of polyarteritis nodosa. Am J Med 67:941-947, 1979
rt
De Novo Systemic Vasculitis in a Renal Transplant Recipient
ROBERT W. SCHRINER, M.D., Division of Thoracic Diseases and Internal Medicine; AARON K. NADA, M.D.,* Division of Nephrology and Internal Medicine; J. T. LIE, M.D., Division of Pathology; MARK P. WILHELM, M.D., Division ofInfectious Diseases and Internal Medicine; SYLVESTER STERIOFF, M.D., Section of Transplantation Surgery; JAMES V. DONADIO, Jr., M.D., Division ofNephrology and Internal Medicine
Abdominal pain, oligoarthritis, macular skin rash, and urine sediment with more than 100 erythrocytes per high-power field and proteinuria developed in a renal transplant recipient who had no prior history of an underlying connective tissue disease. A polyarteritis-type necrotizing vasculitis was detected in the small bowel mesentery. A search for other etiologic factors revealed none. This case demonstrates that de novo vasculitis can develop in renal transplant recipients despite adequate immunosuppressive regimens and may respond to increased dosages of corticosteroids.
Vasculitis has been reported to develop and progress in transplant recipients receiving immunosuppressive therapy.l" In most cases, this condition has occurred in the setting of a recurrent autoimmune vasculitic process-s or an infection. 6-8 We found one previous case report ofa de novo angiitis ofthe central nervous system in a renal transplant recipient who was receiving prednisone and azathioprine." Herein we describe a patient in whom evidence of a systemic vasculitis developed 2 years after he had received a cadaveric renal allograft and while he was taking a triple-drug immunosuppressive regimen. *Current address: John A. Burns School of Medicine, Honolulu, Hawaii. Address reprint requests to Dr. R. W. Schriner, Division of Thoracic Diseases, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 66:183-186, 1991
REPORT OF CASE A 52-year-old man had received a renal allograft in 1987 because of end-stage autosomal dominant polycystic kidney disease. Stable allograft function was maintained with immunosuppressive therapy that consisted of cyclosporine (200 mg twice a day, with whole blood trough levels of 85 and 74 ng/ml; high-performance liquid chromatographic method with a therapeutic range of 100 to 300 ng/ml), azathioprine (150 mg/day), and prednisone (15 mg/day). He was also taking prazosin hydrochloride, furosemide, minoxidil, and atenolol for hypertension. In April 1989, the patient had undergone a left tibial-talar arthrodesis with external fixation because of degenerative joint disease. Routine follow-up 4 weeks later showed that the allograft function was stable (serum creatinine, 1.7 mg/ dl; no microhematuria or proteinuria on urinalysis). During the next 2 days, he noted the
183
184
VASCULITIS IN RENAL TRANSPLANT RECIPIENT
gradual onset of diffuse abdominal pain associated with emesis and melena. The patient was admitted to a local hospital, where a nasogastric aspirate and stool specimens were guaiac positive. An abdominal roentgenogram and computed tomographic scan were unremarkable except for cysts in the liver and native kidney. Cultures of blood and urine specimens for bacteria were negative. The patient was treated with ranitidine hydrochloride, blood transfusion, and cefoxitin sodium. During the next 24 hours, development of a macular rash on the upper torso, paroxysms of abdominal pain, arthralgias and oligoarthritis in the right upper extremity, and hematuria prompted transfer of the patient to our institution. At the time of admission, the physical examination disclosed a row-grade fever (temperature of38.2°C), macular rash without purpura on the upper torso, synovitis of the right elbow, abdominal pain in the left upper quadrant distinct from the left native polycystic kidney, and guaiacpositive stools. The transplanted kidney was nontender to palpation. The left ankle was in an external fixation device, but it was not erythematous or swollen. The findings on neurologic examination were normal. The initial laboratory evaluation revealed a urine sediment that contained more than 100 erythrocytes per high-power field and 1+ proteinuria, an erythrocyte sedimentation rate of 31 mm in 1 hour, and a stable serum creatinine concentration of 1.6 mg/dl. Results of liver function tests (aspartate aminotransferase, 15 U/liter; alkaline phosphatase, 90 U/liter; and bilirubin, 1.1 mg/dl) were normal, as was the serum amylase value (65 U/liter). The hemoglobin concentration was 12.7 g/dl, and the leukocyte count was 9.0 x 103/mm3 • Cultures of blood, urine, and aspirate from the right elbow for bacteria, fungi, and viruses were negative. Analysis of synovial fluid from the right elbow showed a total leukocyte count of 2,704/mm 3 , glucose of 142 mg/dl, and no crystals. An echocardiogram demonstrated no valvular vegetations. Stool examination was negative for bacterial pathogens, and no parasites were seen. Antibodies to Histoplasma capsulatum, Blasto-
Mayo Clin Proc, February 1991, Vol 66
myces dermatitidis, Coccidioides immitis, and human immunodeficiency virus type 1 were not detected. Testing for cryptococcal antigen and IgM antibodies to cytomegalovirus was negative. Subsequent urinalysis showed more than 100 erythrocytes per high-power field, occasional erythrocyte casts, and 2+ proteinuria. Tests for hepatitis B surface antigen, anti-neutrophil cytoplasmic antibodies, antinuclear antibodies, myoglobin, and cryoglobulins were negative. Total complement (81 U; normal, 25 to 110) was normal, but the C3 component was slightly reduced (55 mg/dl; normal, 70 to 150). A chest roentgenogram was unremarkable, but abdominal plain films and a computed tomographic scan showed a dilated and thickwalled loop of small bowel. A barium examination of the small bowel disclosed an 8- to 10-cm proximal jejunal segment that had diffusely thickened folds and was nondistensible. A biopsy specimen obtained on extended esophagogastroduodenoscopy showed an inflammatory ulcer with reactive immunoblastic proliferation. Because of persistent symptoms, a laparotomy was performed; four areas of extensive ulceration involved the proximal jejunum as a result of necrotizing vasculitis of the classic polyarteritis type with fibrinoid necrosis (Fig. 1). Although Candida albicans was recovered in culture, no histopathologic evidence of tissue invasion was found. Cytomegalovirus infection was specifically excluded by tissue immunostaining, culture, and the absence of inclusion bodies. The patient had an uneventful recovery from the surgical procedure. Postoperatively, an increase in the dosage of prednisone from 15 to 60 mg/day resulted in clinical and laboratory improvement. He had no further fevers, abdominal pain, rashes, or joint symptoms. At dismissal, the erythrocyte sedimentation rate had decreased to 7 mm in 1 hour, the urinalysis showed 4 to 10 erythrocytes per high-power field but no proteinuria or erythrocyte casts, and the serum creatinine level was 1.7 mg/dl. The hemoglobin concentration was stable (11 g/dl) postoperatively. During the subsequent 6 months, the patient had a stable clinical course. The dosage of pred-
Mayo Clin Proc, February 1991, Vol 66
Fig. 1. Photomicrograph of a representative polyarteritistype necrotizing vasculitis in the small bowel mesentery of a renal transplant recipient with no underlying connective tissue disease. (Hematoxylin-eosin; x160.)
nisone was gradually decreased to 15 mg/day, and the azathioprine and cyclosporine regimens were maintained.
DISCUSSION Polyarteritis nodosa is a multisystem disorder characterized by a pleomorphic cellular infiltration and fibrinoid necrosis of small and mediumsized arteries.P-" The pathogenesis is unknown, but postulated mechanisms include arterial deposition of soluble immune complexes or cellmediated immune processes. The widespread distribution of the arterial lesions in polyarteritis nodosa produces diverse clinical manifestations. In autopsy series, involvement is noted in the kidneys and heart in
VASCULITIS IN RENAL TRANSPLANT RECIPIENT
185
about 70% of cases; in the liver, gastrointestinal tract, and peripheral nerves in 50%; in the mesentery and skeletal muscle in approximately 20%; and in the skin in 5 to 50%.10,11 Laboratory findings are nonspecific but usually include an increased erythrocyte sedimentation rate, anemia, leukocytosis, and abnormal urine sediment when renal involvement is present. Serum cryoglobulins, rheumatoid factor, hepatitis B antigenemia, and diminished concentrations of serum whole complement are observed in 10 to 25% of patients. 11 Conditions that simulate necrotizing vasculitis clinically include left atrial myxoma, infective endocarditis, septicemia, Lyme disease, lymphoma, cholesterol embolization from a largeartery aneurysm, and drug hypersensitivity.l" In the immunocompromised host, cytomegalovirus infection and disseminated cryptococcosis must also be considered in the differential diagnosis.v" These conditions were specifically excluded in the current case. In the polyarteritis nodosa group of systemic vasculitis, corticosteroids are the mainstay of therapy, but a few retrospective studies have shown improved survival with the addition of cyclophosphamide or azathioprine.Pv" The published literature has a paucity of information about the treatment of an autoimmune vasculitic process in a patient already receiving an immunosuppressive regimen. Steinman and associates' reported a dramatic response in a renal transplant recipient with recurrent Wegener's granulomatosis who was treated with an increase in dosage of prednisone from 10 to 40 mg/day and a switch from azathioprine, 150 mgt day, to cyclophosphamide, 150 mg/day. A similar case of recurrent Wegener's granulomatosis seemed to respond to the replacement of azathioprine by cyclophosphamide. 3 In another patient with recurrent Wegener's granulomatosis, however, renal allograft function did not improve by a change from azathioprine to cyclophosphamide, but the duration of treatment' with cyclophosphamide was limited because of a complicating Listeria meningitis." Rothenberg" described a poor response of central nervous system angiitis in a renal transplant recipient to
186
VASCULITIS IN RENAL TRANSPLANT RECIPIENT
treatment that included increasing the dosage of prednisone from 15 to 60 mg/day and substituting cyclophosphamide for azathioprine. Because our patient was doing well after laparotomy and augmentation of his corticosteroid therapy, we elected to continue administering high-dose prednisone for at least 1 month followed by a gradual taper of the dose. This strategy was successful in achieving a quiescent stage.
CONCLUSION An immunologically mediated disease process developed in a renal transplant recipient without an underlying connective tissue disease while he was receiving effective transplant immunosuppressive therapy. This case illustrates that recurrent or de novo vasculitis cannot be excluded in the differential diagnosis of conditions that occur in transplant recipients. In such patients with evidence of vasculitis, an accurate diagnosis is necessary because further management involves increasing the dosage of corticosteroids and perhaps changing cytotoxic agentsfor example, from azathioprine to cyclophosphamide-if a clinical response is not obtained with corticosteroid treatment. REFERENCES 1. Steinman TI, Jaffe BF, Monaco AP, WolffSM, Fauci AS: Recurrence of Wegener's granulomatosis after kidney transplantation: successful re-induction of remission with cyclophosphamide. Am J Med 68:458460, 1980 2. Duvall AJ III, Nelms CR, Williams HL: Necrotizing granuloma of the midline tissues following renal
Mayo Clin Proc, February 1991, Vol 66
3. 4.
5. 6.
7.
8.
9. 10. 11.
12.
13. 14.
transplantation. Trans Am Acad Ophthalmol Otolaryngol 73:1187-1207,1969 Salaman R, Coles GA, Saltissi D: Haemodialysis and transplantation in Wegener's granulomatosis (letter to the editor). Br Med J 280:254, 1980 Curtis JJ, Diethelm AG, Herrera GA, Crowell WT, Whelchel JD: Recurrence of Wegener's granulomatosis in a cadaver renal allograft. Transplantation 36:452-454, 1983 Rothenberg RJ: Isolated angiitis of the brain: case in a renal transplant recipient. Am J Med 79:629-632, 1985 Shrader SK, Watts JC, Dancik JA, Band JD: Disseminated cryptococcosis presenting as cellulitis with necrotizing vasculitis. J Clin Microbiol 24:860-862, 1986 Minars N, Silverman JF, Escobar MR, Martinez AJ: Fatal cytomegalic inclusion disease: associated skin manifestations in a renal transplant patient. Arch Dermatol 113:1569-1571, 1977 Foucar E, Mukai K, Foucar K, Sutherland DER, Van Buren CT: Colon ulceration in lethal cytomegalovirus infection. Am J Clin Pathol 76:788-801, 1981 Zeek PM: Periarteritis nodosa and other forms of necrotizing angiitis. N Engl J Med 248:764-772, 1953 Lie JT: Systemic and isolated vasculitis: a rational approach to classification and pathologic diagnosis. Pathol Annu 24 (Part 1):25-114, 1989 Cohen RD, Conn DL, Ilstrup DM: Clinical features, prognosis, and response to treatment in polyarteritis. Mayo Clin Proc 55:146-155,1980 Conn DL, Hunder GG: Vasculitis and related disorders. In Textbook of Rheumatology. Third edition. Edited by WN Kelley, ED Harris Jr, S Ruddy, CB Sledge. Philadelphia, WB Saunders Company, 1989, pp 1167-1199 Fauci AS, Katz P, Haynes BF, Wolff SM: Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med 301:235-238, 1979 Leib ES, Restivo C, Paulus HE: Immunosuppressive and corticosteroid therapy of polyarteritis nodosa. Am J Med 67:941-947, 1979
