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Treatment of Wegener's granulomatosis with Imuran
Treatment
of Wegener’s
Granulomatosis
with Imuran* BERTHA
A. BOURONCLE,
M.D., EDWIN J. SMITH,
M.D. and FRANCIS
E. CUPPAGE,
M.D.
A patient with Wegener’s granulomatosis experienced a remarkable regression on continuous therapy with Imuran@, with control of lesions in sinuses, lungs and kidneys after one year.
W
when bilateral ear infections developed. In November 1964 he began to have episodes of epistaxis and nasal discharge, and had repeated cauterizations of his nose. On January 9, 1965, he was hospitalized elsewhere for recurring profuse epistaxis, anemia and productive cough; he received nine blood transfusions and was treated with antibiotics. A vessel ligation was performed in an attempt to control the epistaxis, but he continued to bleed profusely from his nose. He was then referred to the Ohio State University Hospital and admitted on February 22, 1965. His chief complaints on admission were persistent epistaxis and productive cough. On physical examination he was a well nourished and well developed white man. The blood pressure was 130/65 mm. Hg, pulse 88 per minute, respirations 18 per minute and temperature 98.5’F. He had a productive cough and brought up large amounts of mucus. The skin over his trunk and arms was the site of raised erythematous areas with serpiginous borders. The areas over his hands were pruritic and ulcerative. The external nares contained blood clots. There was crusting and ulceration in the concavity of the septum, which was deviated. The posteroanterior diameter of the chest was increased. Examination of the lungs revealed numerous rhonchi. The heart was normal. The lymph nodes were not enlarged. The spleen and liver were normal. The neurologic examination was within normal limits. Examination of the peripheral blood showed a total white blood cell count of 5,950 per cu. mm. with a differential of 76 per cent polymorphonuclears, 3 per cent basophils, 1 per cent eosinophils, 18 per cent small lymphocytes and 2 per cent monocytes; total red blood cell count was 3,100,OOO per cu. mm., hemoglobin 9.6 gm. per cent, reticulocytes 1.2 per cent and platelets 446,400 per cu. mm. Bone marrow was aspirated from the sternum and numerous fragments were obtained. Microscopic examination showed an active bone marrow which was essentially normal
EGENER’S granulomatosiswas first described in 1931 by Klinger [I], who reported the autopsy findings in two cases, and later by Wegener in 1936 [2,3]. Both investigators believed that this was a disease entity. Subsequently, over two hundred cases have been reported. The disease is characterized by a necrotizing granulomatous lesion in the upper airway or lower respiratory tract or both, widespread focal vasculitis and necrotizing glomerulitis. It has been considered by some to be a variant of periarteritis nodosa. It is usually a fatal disease, with an average life span of six months to one year. Recently there have been several reports on the therapeutic value of corticosteroids in this disease. The reports are contradictory [&?I, and the use of steroids in general has been of limited value, with multiple side effects [9]. As a consequence we decided to try Imuran@. In this compound, related to 6-mercaptopurine, an imidazole ring replaces the hydrogen of the sulfhydryl group of 6-mercaptopurine. It has proved to be as effective as 6-mercaptopmine in the treatment of some tumors in animals and in chronic granulocytic leukemia in man [70], and to have a superior immunosuppressive effect [ 17-741 and lower toxicity [ 751 than 6-mercaptopurine. The results we obtained with Imuran therapy in a patient with Wegener’s granulomatosis were so encouraging that we wish to record them. CASE REPORT This miner,
sixty-five year old white man, a retired had enjoyed good health until August
coal 1964
* From the Departments of Medicine and Pathology, Ohio State University, Columbus, Ohio. This investigation was supported by Grant No. T-341, from the American Cancer Society. Imuran, 6-(l-methyl-4-nitro-5-imidazolyl)thiopurine, B.W. 57-322, azathioprine was provided by Burroughs Wellcome & Co., through the courtesy of Dr. Donald
S. Searly.
Manuscript
received
May
9, 1966.
314
AMERICAN
JOURNAL
OF
MEDICINE
Wegener’s 2-23-65 TOTAL
PROTEIN
Granulomatosis-~~Hi,uronc,/e L? (11.
3-23-66 am.%
7.6
_~~~~~~~
7.4
ALBUMIN% ALPHA-I %
21.6 9.1
-~ ~ ~~~~_~~~~~~~_
ALPHA-2%
11.4
--~~~~~~
15.3
-~-
BETA% GAMMA%
42.6
60.7 3.1
---
7.4 6.0 -
16.9
FIG. 1. Serum electrophoretic pattern before and one year after therapy with Imuran, demonstrating a marked decrease in gamma globulin and increase in albumin. for all three elements, with moderate normoblastic hyperplasia. There was a slight increase in plasma cells which were morphologically normal. The direct Coombs’ test was 3+. Serum iron was 65 mg. per cent. The clotting time in the first tube was twelve minutes, second tube thirteen minutes and third tube fifteen minutes. Clot retraction was good. The prothrombin time was 86 per cent and the partial thromboplastin time was 39.1 seconds. Numerous erythrocytes were present in the sediment of repeated urine specimens. The twenty-four hour urine total protein was 160 mg. The blood urea nitrogen was 12 mg. per cent, the serum creatinine was 0.8 mg. per cent. The serum total protein was 7.6 gm. per cent with albumin 3.4 and globulin 4.2 gm. per cent. Serum electrophoresis showed a diffuse increase in gamma globulin (Fig. 1). The serum alkaline phosphatase was 6.8 units, inorganic phosphorus 3.2 mg. per cent, serologic tests for syphilis were negative. The serum calcium was 4.3 mEq. per L. The latex fixation test was negative. The fasting blood sugar was 98 mg. per cent. The serum glutamic oxalacetic transaminase @GOT) was 25 units, lactic dehydrogenase was 250 units. Lupus erythematosus preparations were negative, serum acid phosphatase 0.6 units, serum total bilirubin 0.7 mg. per cent, bromsulfalein retention was 3.7 per cent in forty-five minutes. The twenty-four hour urinary urobilinogen excretion was 16.6 mg. Urine cultures revealed the presence of a moderate growth of Proteus and a light growth of a coliform. Sensitivity tests proved these organisms to be sensitive to Cephalothin@ and the patient was treated with this medication during his hospitalization. Urine cultures taken after the discontinuation of therapy were negative. The patient proved to be allergic to penicillin which had been given prior to his admission to our hospital and he still had a skin rash when first seen. Numerous sputum cultures for bacteria and tubercle bacilli were negative. A biopsy specimen from the lesion of the nasal septum revealed subacute inflammation of the mucosa and submucosa. The cellular infiltrate extended to the “01..
42,
FEBRUARY
1967
FIG. 2. Chest roentgcnogram prior to the initiation of Imuran therapy drmonstrating extensive hilatrral nodular patchy and granular pulmonary infiltration, with additional pulmonary infiltration around troth hilar areas.
FIG. 3. Roentgenogram of sinuses prior to initiation of Imuran therapy demonstrating complete opacification of the maxillary antrum and frontal sinuses. There is a soft tissue density mass in the middle and posterior ethmoid cell area on the right side showing cell destruction, secondary obstruction and infection involving the frontal and maxillary sinuses on the same sidr
316
Wegener’s
Granulomatosis-Bouroncle
et al.
Fro. 5. Chest roentgenogram one year after Imuran therapy showing practically complete clearing of the infiltrative lesions previously seen.
FIG. 4. Initial renal biopsy specimen. Note the prominent foci of inflammatory cells in the interstitium and the tubular degeneration. Hematoxylin and eosin stain, original magnification X 225.
FIG. 6. Roentgenogram of sinuses one year after Imuran therapy showing marked clearing of the opacification of sinuses, without bone destruction.
FIG. 7. Repeat renal biopsy specimen obtained one year after Imuran therapy. In contrast to the initial biopsy specimen, less cellular response is noted in the interstitium and glomcruli. Focal interstitial fibrosis and tubular atrophy are shown. Hematoxylin and eosin stain, original magnification X 225.
Wegener’s
Granulomatosis--Bourorzcle
depth of the biopsy specimen and consisted of polymorphonuclear leukocytes, lymphocytes and plasma cells. Dense hyalinized connective tissue enclosed the mucosa glands. The chest roentgenogram revealed extensive bilateral finely distributed nodular, patchy and granular pulmonary infiltrates with an additional superimposed pulmonary infiltrate around both hilar areas (Fig. 2). The roentgenogram of the paranasal sinuses showed complete opacification of the maxillary antrum and frontal sinuses. There was also a soft tissue density mass in the middle and posterior ethmoid cell area on the right side showing some cell destruction and secondary obstruction, infection involving the frontal and maxillary sinuses on the same side (Fig. 3). Metastatic bone survey, intravenous pyelogram and gastroduodenal roentgenograms were normal. A renal biopsy was performed on March 11, 1965 (Fig. 4). The kidney tissue contained numerous areas of dense interstitial infiltration with polymorphonuclear leukocytes, lymphocytes and plasma cells. Some of these areas of infiltration exhibited necrotic centers and had the appearance of necrotizing granulomas. Focal glomerular hypercellularity and hyalinization, and tubular degeneration were also prominent. On March 16, 1965, the administration of Imuran, 150 mg. daily, was begun. On April 4, 1965, the patient was readmitted to our hospital because of anemia and he was given four blood transfusions. He continued to receive Imuran therapy, 150 mg. daily, until May 12, 1965, at which time the dosage was decreased to 100 mg. daily; this dose has been continued to the present. After approximately two months of Imuran therapy, there was marked improvement in the patient’s general health. The blood picture, which has shown marked anemia with a hemoglobin as low as 5.5 gm. per cent and 1,920,OOO red blood cells per cu. mm. on April 14,1965, improved and the hemoglobin rose to levels of 10.5 to 11.0 gm. per cent by July 1965 and remained there without further blood transfusions. The epistaxis subsided, the coughing diminished and the patient was able to lead a normal life at home. On March 21, 1966, after a year on Imuran therapy, the patient was readmitted to the Ohio State University Hospital for re-evaluation. His peripheral blood count on this admission showed a total white blood cell count of 3,000 per cu. mm. with a supravital differential of 76 per cent polymorphonuclear leukocytes, 1 per cent basophils, 2 per cent eosinophils, 20 per cent small lymphocytes and 1 per cent monocytes; the total red blood cell count was 3,250,OOO per cu. mm. with 10.7 gm. of hemoglobin, reticulocytes 1.6 per cent ar?d platelets 630,500 per cu. mm. The direct Coombs’ test \vas negative. Serum electrophoresis sho\ved a mar!
42,
FEBRUARY
1967
et al.
317
ing of the infiltrative lesions previously je?Ik (Fig. 5). Roentgenograms of the sinuses showed marked clearing of opacification without bone destruction (Fig. 6). A kidney biopsy was repeated follo\ving the year of Imuran therapy. Less activity was noted in the interstitium examined. Fewer aggregates of inflammatory cells were present. The interstitium rontained more fibrous connective tissue. Glomerular hyalinization and tubular atrophy were more prominent. Less glomerular hypercellularity was observed (F’ig. 7). COMMENTS Spontaneous
regressions
of
severe
and
ex-
have not been reported. Corticosteroids may temporarily limit the spread of lesions, but they fail to control the disease, and complications of corticosteroid therapy frequently occur. The prolonged response of one year’s duration in our patient treated with Imuran is exceptional. Treatment of M’egener’s granulomatosis with Imuran has not been reported previously, so far as we could ascertain. Reports of two patients with lethal midline granuloma successfully treated with cyclophosphamidc and steroids, and with intra-arterial infusion of mexthotraxate, respectively, have been recorded [ 76,77]. The immunosuppressive effect of Imuran therapy was evidenced in this patient by the marked decrease in gamma globulins (Fig. 1) and reversal of the direct Coombs’ test to negative after one year of continuous therap>-. The decrease in activity of the nasal, pulmonary and renal lesions lnay also correspond to this immunosuppressive effect. tensive
Wegener’s
granulonlatosis
REFERENCES 1. KLINGER, N. Grenzformen der Periarteritis nodosa. Frankfurt. Ztschr. Path., 42: 455, 1931. 2. WEGENER, F. Ueber generalisierte, septische Gef&erkrankungen. Verhandl. deutxh. path. Gmellsch., 29: 202, 1936. 3. WEGENER, F. Ueber eine eigenartige rhinogene Granulomatose mit besonderer Beteiligung des Arterien Systems und der Nieren. Reztr. path. Amt., 102: 36, 1939. 4. WALTON, E. W. Giant-cell granuloma of respiratory tract (Wegener’s granulomatosisj. Rrit. M. J., 2: 265, 1958. 5. TUHY, J. E., MAURICE, G. L. and NILES, N. R. Wegener’s granulomatosis. Am. J. Med., 25: 638, 1958. 6. FELSON, B. Less familiar roentgen patterns of pulmonary granulomas. Am. J. Roentgenol., 81: 211, 1959. 7. BISCHOFT, M. E. Noninfectious necrotizing granulomatosis: pulmonary roentgen signs. Radiology, 75: 752, 1960. 8. SPROUL, E. E. Wegener’s and lethal midline granulomatosis. J.A.M.A.. 177: 921 1961.
318
Wegener’s
Granulomatosis-Bouroncle
9. BEIDLEMAN,B. Wegener’s granulomatosis. Prolonged therapy with large doses of steroids. J.A.M.A., 186: 67, 1963. 10. RUNDLES, R. W., LASZLO, J., ITOGA, T., HOBSON, J. B. and GARRISON, F. E., JR. Clinical and hematologic study of 6-( I-methyl-4-nitro-5-imidazolyl thiopurine) (B.W. 57-322) and related compounds. Cancer Chemo. Rejmrts, 14: 99, 1961. 11. AISENBERG, A. C. Drugs employed for the suppression of immunologic responsiveness. New England J. Med., 272: 1114, 1965. 12. CALNE, R. Y. Inhibition of the rejection of renal homografts in dogs by purine analogues. Tramplantation Bull., 28: 65, 1961. 13. NATHAN, H. C., BIEBER,S., ELION, G. B. and HITCH-
14. 15.
16.
17.
et al.
INGS, G. H. Detection of agents which interfere with the immune response. Sac. Exper. Biol. G? Med., 107: 796, 1961. MURRAY, J. E. Human kidney transplant conference. Trans&zntation, 3: 147, 1964. BOURONCLE,B. A. and DOAN, C. A. Treatment of refractory idiopathic thrombocytopenic purpura and acquired hemolytic anemia with Imuran. New England J. Med., 275: 630, 1966. GREENSPAN, E. M. Cyclophosphamide-prednisone therapy of lethal midline granuloma. J.A.M.A., 193: 162, 1965. VON LEDEN, H. and SCHIFF, M. Antimetabolite therapy in lethal midline granuloma. Arch. Otolaryng., 80: 460. 1964.
AMERICAN
JOURNAL
OF
MEDICINE
of Wegener’s
Granulomatosis
with Imuran* BERTHA
A. BOURONCLE,
M.D., EDWIN J. SMITH,
M.D. and FRANCIS
E. CUPPAGE,
M.D.
A patient with Wegener’s granulomatosis experienced a remarkable regression on continuous therapy with Imuran@, with control of lesions in sinuses, lungs and kidneys after one year.
W
when bilateral ear infections developed. In November 1964 he began to have episodes of epistaxis and nasal discharge, and had repeated cauterizations of his nose. On January 9, 1965, he was hospitalized elsewhere for recurring profuse epistaxis, anemia and productive cough; he received nine blood transfusions and was treated with antibiotics. A vessel ligation was performed in an attempt to control the epistaxis, but he continued to bleed profusely from his nose. He was then referred to the Ohio State University Hospital and admitted on February 22, 1965. His chief complaints on admission were persistent epistaxis and productive cough. On physical examination he was a well nourished and well developed white man. The blood pressure was 130/65 mm. Hg, pulse 88 per minute, respirations 18 per minute and temperature 98.5’F. He had a productive cough and brought up large amounts of mucus. The skin over his trunk and arms was the site of raised erythematous areas with serpiginous borders. The areas over his hands were pruritic and ulcerative. The external nares contained blood clots. There was crusting and ulceration in the concavity of the septum, which was deviated. The posteroanterior diameter of the chest was increased. Examination of the lungs revealed numerous rhonchi. The heart was normal. The lymph nodes were not enlarged. The spleen and liver were normal. The neurologic examination was within normal limits. Examination of the peripheral blood showed a total white blood cell count of 5,950 per cu. mm. with a differential of 76 per cent polymorphonuclears, 3 per cent basophils, 1 per cent eosinophils, 18 per cent small lymphocytes and 2 per cent monocytes; total red blood cell count was 3,100,OOO per cu. mm., hemoglobin 9.6 gm. per cent, reticulocytes 1.2 per cent and platelets 446,400 per cu. mm. Bone marrow was aspirated from the sternum and numerous fragments were obtained. Microscopic examination showed an active bone marrow which was essentially normal
EGENER’S granulomatosiswas first described in 1931 by Klinger [I], who reported the autopsy findings in two cases, and later by Wegener in 1936 [2,3]. Both investigators believed that this was a disease entity. Subsequently, over two hundred cases have been reported. The disease is characterized by a necrotizing granulomatous lesion in the upper airway or lower respiratory tract or both, widespread focal vasculitis and necrotizing glomerulitis. It has been considered by some to be a variant of periarteritis nodosa. It is usually a fatal disease, with an average life span of six months to one year. Recently there have been several reports on the therapeutic value of corticosteroids in this disease. The reports are contradictory [&?I, and the use of steroids in general has been of limited value, with multiple side effects [9]. As a consequence we decided to try Imuran@. In this compound, related to 6-mercaptopurine, an imidazole ring replaces the hydrogen of the sulfhydryl group of 6-mercaptopurine. It has proved to be as effective as 6-mercaptopmine in the treatment of some tumors in animals and in chronic granulocytic leukemia in man [70], and to have a superior immunosuppressive effect [ 17-741 and lower toxicity [ 751 than 6-mercaptopurine. The results we obtained with Imuran therapy in a patient with Wegener’s granulomatosis were so encouraging that we wish to record them. CASE REPORT This miner,
sixty-five year old white man, a retired had enjoyed good health until August
coal 1964
* From the Departments of Medicine and Pathology, Ohio State University, Columbus, Ohio. This investigation was supported by Grant No. T-341, from the American Cancer Society. Imuran, 6-(l-methyl-4-nitro-5-imidazolyl)thiopurine, B.W. 57-322, azathioprine was provided by Burroughs Wellcome & Co., through the courtesy of Dr. Donald
S. Searly.
Manuscript
received
May
9, 1966.
314
AMERICAN
JOURNAL
OF
MEDICINE
Wegener’s 2-23-65 TOTAL
PROTEIN
Granulomatosis-~~Hi,uronc,/e L? (11.
3-23-66 am.%
7.6
_~~~~~~~
7.4
ALBUMIN% ALPHA-I %
21.6 9.1
-~ ~ ~~~~_~~~~~~~_
ALPHA-2%
11.4
--~~~~~~
15.3
-~-
BETA% GAMMA%
42.6
60.7 3.1
---
7.4 6.0 -
16.9
FIG. 1. Serum electrophoretic pattern before and one year after therapy with Imuran, demonstrating a marked decrease in gamma globulin and increase in albumin. for all three elements, with moderate normoblastic hyperplasia. There was a slight increase in plasma cells which were morphologically normal. The direct Coombs’ test was 3+. Serum iron was 65 mg. per cent. The clotting time in the first tube was twelve minutes, second tube thirteen minutes and third tube fifteen minutes. Clot retraction was good. The prothrombin time was 86 per cent and the partial thromboplastin time was 39.1 seconds. Numerous erythrocytes were present in the sediment of repeated urine specimens. The twenty-four hour urine total protein was 160 mg. The blood urea nitrogen was 12 mg. per cent, the serum creatinine was 0.8 mg. per cent. The serum total protein was 7.6 gm. per cent with albumin 3.4 and globulin 4.2 gm. per cent. Serum electrophoresis showed a diffuse increase in gamma globulin (Fig. 1). The serum alkaline phosphatase was 6.8 units, inorganic phosphorus 3.2 mg. per cent, serologic tests for syphilis were negative. The serum calcium was 4.3 mEq. per L. The latex fixation test was negative. The fasting blood sugar was 98 mg. per cent. The serum glutamic oxalacetic transaminase @GOT) was 25 units, lactic dehydrogenase was 250 units. Lupus erythematosus preparations were negative, serum acid phosphatase 0.6 units, serum total bilirubin 0.7 mg. per cent, bromsulfalein retention was 3.7 per cent in forty-five minutes. The twenty-four hour urinary urobilinogen excretion was 16.6 mg. Urine cultures revealed the presence of a moderate growth of Proteus and a light growth of a coliform. Sensitivity tests proved these organisms to be sensitive to Cephalothin@ and the patient was treated with this medication during his hospitalization. Urine cultures taken after the discontinuation of therapy were negative. The patient proved to be allergic to penicillin which had been given prior to his admission to our hospital and he still had a skin rash when first seen. Numerous sputum cultures for bacteria and tubercle bacilli were negative. A biopsy specimen from the lesion of the nasal septum revealed subacute inflammation of the mucosa and submucosa. The cellular infiltrate extended to the “01..
42,
FEBRUARY
1967
FIG. 2. Chest roentgcnogram prior to the initiation of Imuran therapy drmonstrating extensive hilatrral nodular patchy and granular pulmonary infiltration, with additional pulmonary infiltration around troth hilar areas.
FIG. 3. Roentgenogram of sinuses prior to initiation of Imuran therapy demonstrating complete opacification of the maxillary antrum and frontal sinuses. There is a soft tissue density mass in the middle and posterior ethmoid cell area on the right side showing cell destruction, secondary obstruction and infection involving the frontal and maxillary sinuses on the same sidr
316
Wegener’s
Granulomatosis-Bouroncle
et al.
Fro. 5. Chest roentgenogram one year after Imuran therapy showing practically complete clearing of the infiltrative lesions previously seen.
FIG. 4. Initial renal biopsy specimen. Note the prominent foci of inflammatory cells in the interstitium and the tubular degeneration. Hematoxylin and eosin stain, original magnification X 225.
FIG. 6. Roentgenogram of sinuses one year after Imuran therapy showing marked clearing of the opacification of sinuses, without bone destruction.
FIG. 7. Repeat renal biopsy specimen obtained one year after Imuran therapy. In contrast to the initial biopsy specimen, less cellular response is noted in the interstitium and glomcruli. Focal interstitial fibrosis and tubular atrophy are shown. Hematoxylin and eosin stain, original magnification X 225.
Wegener’s
Granulomatosis--Bourorzcle
depth of the biopsy specimen and consisted of polymorphonuclear leukocytes, lymphocytes and plasma cells. Dense hyalinized connective tissue enclosed the mucosa glands. The chest roentgenogram revealed extensive bilateral finely distributed nodular, patchy and granular pulmonary infiltrates with an additional superimposed pulmonary infiltrate around both hilar areas (Fig. 2). The roentgenogram of the paranasal sinuses showed complete opacification of the maxillary antrum and frontal sinuses. There was also a soft tissue density mass in the middle and posterior ethmoid cell area on the right side showing some cell destruction and secondary obstruction, infection involving the frontal and maxillary sinuses on the same side (Fig. 3). Metastatic bone survey, intravenous pyelogram and gastroduodenal roentgenograms were normal. A renal biopsy was performed on March 11, 1965 (Fig. 4). The kidney tissue contained numerous areas of dense interstitial infiltration with polymorphonuclear leukocytes, lymphocytes and plasma cells. Some of these areas of infiltration exhibited necrotic centers and had the appearance of necrotizing granulomas. Focal glomerular hypercellularity and hyalinization, and tubular degeneration were also prominent. On March 16, 1965, the administration of Imuran, 150 mg. daily, was begun. On April 4, 1965, the patient was readmitted to our hospital because of anemia and he was given four blood transfusions. He continued to receive Imuran therapy, 150 mg. daily, until May 12, 1965, at which time the dosage was decreased to 100 mg. daily; this dose has been continued to the present. After approximately two months of Imuran therapy, there was marked improvement in the patient’s general health. The blood picture, which has shown marked anemia with a hemoglobin as low as 5.5 gm. per cent and 1,920,OOO red blood cells per cu. mm. on April 14,1965, improved and the hemoglobin rose to levels of 10.5 to 11.0 gm. per cent by July 1965 and remained there without further blood transfusions. The epistaxis subsided, the coughing diminished and the patient was able to lead a normal life at home. On March 21, 1966, after a year on Imuran therapy, the patient was readmitted to the Ohio State University Hospital for re-evaluation. His peripheral blood count on this admission showed a total white blood cell count of 3,000 per cu. mm. with a supravital differential of 76 per cent polymorphonuclear leukocytes, 1 per cent basophils, 2 per cent eosinophils, 20 per cent small lymphocytes and 1 per cent monocytes; the total red blood cell count was 3,250,OOO per cu. mm. with 10.7 gm. of hemoglobin, reticulocytes 1.6 per cent ar?d platelets 630,500 per cu. mm. The direct Coombs’ test \vas negative. Serum electrophoresis sho\ved a mar!
42,
FEBRUARY
1967
et al.
317
ing of the infiltrative lesions previously je?Ik (Fig. 5). Roentgenograms of the sinuses showed marked clearing of opacification without bone destruction (Fig. 6). A kidney biopsy was repeated follo\ving the year of Imuran therapy. Less activity was noted in the interstitium examined. Fewer aggregates of inflammatory cells were present. The interstitium rontained more fibrous connective tissue. Glomerular hyalinization and tubular atrophy were more prominent. Less glomerular hypercellularity was observed (F’ig. 7). COMMENTS Spontaneous
regressions
of
severe
and
ex-
have not been reported. Corticosteroids may temporarily limit the spread of lesions, but they fail to control the disease, and complications of corticosteroid therapy frequently occur. The prolonged response of one year’s duration in our patient treated with Imuran is exceptional. Treatment of M’egener’s granulomatosis with Imuran has not been reported previously, so far as we could ascertain. Reports of two patients with lethal midline granuloma successfully treated with cyclophosphamidc and steroids, and with intra-arterial infusion of mexthotraxate, respectively, have been recorded [ 76,77]. The immunosuppressive effect of Imuran therapy was evidenced in this patient by the marked decrease in gamma globulins (Fig. 1) and reversal of the direct Coombs’ test to negative after one year of continuous therap>-. The decrease in activity of the nasal, pulmonary and renal lesions lnay also correspond to this immunosuppressive effect. tensive
Wegener’s
granulonlatosis
REFERENCES 1. KLINGER, N. Grenzformen der Periarteritis nodosa. Frankfurt. Ztschr. Path., 42: 455, 1931. 2. WEGENER, F. Ueber generalisierte, septische Gef&erkrankungen. Verhandl. deutxh. path. Gmellsch., 29: 202, 1936. 3. WEGENER, F. Ueber eine eigenartige rhinogene Granulomatose mit besonderer Beteiligung des Arterien Systems und der Nieren. Reztr. path. Amt., 102: 36, 1939. 4. WALTON, E. W. Giant-cell granuloma of respiratory tract (Wegener’s granulomatosisj. Rrit. M. J., 2: 265, 1958. 5. TUHY, J. E., MAURICE, G. L. and NILES, N. R. Wegener’s granulomatosis. Am. J. Med., 25: 638, 1958. 6. FELSON, B. Less familiar roentgen patterns of pulmonary granulomas. Am. J. Roentgenol., 81: 211, 1959. 7. BISCHOFT, M. E. Noninfectious necrotizing granulomatosis: pulmonary roentgen signs. Radiology, 75: 752, 1960. 8. SPROUL, E. E. Wegener’s and lethal midline granulomatosis. J.A.M.A.. 177: 921 1961.
318
Wegener’s
Granulomatosis-Bouroncle
9. BEIDLEMAN,B. Wegener’s granulomatosis. Prolonged therapy with large doses of steroids. J.A.M.A., 186: 67, 1963. 10. RUNDLES, R. W., LASZLO, J., ITOGA, T., HOBSON, J. B. and GARRISON, F. E., JR. Clinical and hematologic study of 6-( I-methyl-4-nitro-5-imidazolyl thiopurine) (B.W. 57-322) and related compounds. Cancer Chemo. Rejmrts, 14: 99, 1961. 11. AISENBERG, A. C. Drugs employed for the suppression of immunologic responsiveness. New England J. Med., 272: 1114, 1965. 12. CALNE, R. Y. Inhibition of the rejection of renal homografts in dogs by purine analogues. Tramplantation Bull., 28: 65, 1961. 13. NATHAN, H. C., BIEBER,S., ELION, G. B. and HITCH-
14. 15.
16.
17.
et al.
INGS, G. H. Detection of agents which interfere with the immune response. Sac. Exper. Biol. G? Med., 107: 796, 1961. MURRAY, J. E. Human kidney transplant conference. Trans&zntation, 3: 147, 1964. BOURONCLE,B. A. and DOAN, C. A. Treatment of refractory idiopathic thrombocytopenic purpura and acquired hemolytic anemia with Imuran. New England J. Med., 275: 630, 1966. GREENSPAN, E. M. Cyclophosphamide-prednisone therapy of lethal midline granuloma. J.A.M.A., 193: 162, 1965. VON LEDEN, H. and SCHIFF, M. Antimetabolite therapy in lethal midline granuloma. Arch. Otolaryng., 80: 460. 1964.
AMERICAN
JOURNAL
OF
MEDICINE