Acta med. scand. Vol. 187, pp. 7-9, 1970

IMMUNOSUPPRESSIVE THERAPY IN WEGENERS GRANULOMATOSIS

Per Teisberg and Erik Enger

From Medical Department V11, Ullevdl Hospital, Oslo, Norway

Abstract. The caFe history of a 26-year-old woman with Wegener’s granulomatosis is presented. There were clini- cal signs of cutaneous, pulmonary, mastoidal and renal involvements. During an oliguric period of five weeks life was maintained by peritoneal dialysis. Eventually she responded favourably to combined treatment with azathio- prine and corticosteroids. During one year’s follow-up the serum creatinine level has remained unchanged at about 2 mg/100 ml. There has also been a marked improvement of the other manifestations of the disease, and her general condition is good.

Wegener’s granulomatosis is a systemic disease which mainly affects upper and lower respiratory tracts and the kidney. It was first described by Klinger in 1931 (7), but was recognized as a clini- cal and pathological syndrome by Wegener a few years later (10, 11). Up to 1967 about 200 cases had bem reported. The disease is charac- terized by necrotizing granulomatous lesions in the airways, focal necrotizing glomerulonephritis and generalized angiitis.

Symptoms and signs from the upper and lower respiratory tracts usually dominate in the early stages of the disease. Clinical signs of renal in- volvement are associated with rapid development of uraemia. The general picture includes fever, leucocytosis and an elevated sedimentation rate.

The aetiology is unknown, but it is assumed that immunological mechanisms are of definite pathogenetic significance.

It is the general experience that Wegener’s granulomatosis is an invariably fatal disease with an average duration of 6-12 months. Recent re- ports, however, indicate favourable results with immunosuppressive therapy in a few cases. In these patients there have been only moderate signs of renal affection. We shall therefore report a case of Wegener’s granulomatosis in an advanced stage of renal failure successfully treated with an irn- munosuppressive regimen.

CASE REPORT The patient is a 26-year-old married woman whose first child was born in October 1967. Her appendix had been removed in 1952, otherwise she had previously been healthy.

Early symptoms and signs In November 1967 the patient noticed a small tumour in the appendicectomy scar. Two months later this per- forated spontaneously with some secretion on the follow- ing days. In January 1968 the tumour was removed and histological sections contained necrotizing giant cell granulomas. The sections did not allow any exact di- agnosis. Blood tests revealed a normal haemoglobin con- tent and ESR. There was, however, blood and protein in the urine.

In the middle of February 1968 she developed symptoms of left-sided otitis media. Treatment with repeated para- centeses and antibiotics had no effect. One month later she suddenly developed paresis of the left facial nerve, and was therefore admitted to the Department of Oto-, Rhino-, Laryngology of this hospital on March 15. Upon admission signs of left-sided mastoiditis and a facial nerve palsy of peripheral type were found. There was still secretion from the surgical wound on her abdomen. The ESR was slightly elevated and she was moderately an- aemic. The urine was normal on chemical examination.

She received massive antibiotic therapy. Mastoidectomy was done twice and surgical decompression of the facial nerve was attempted. None of these procedures had any effect. Repeated search for acid-fast organisms in secre- tions from the ear and from the abdominal wound were negative. Histological sections of the material removed during mastoidectomy contained necrotic fragments of bone and granulation tissue with signs of chronic inflam- mation.

There was a steady deterioration of her clinical con- dition. She was slightly febrile and the ESR rose to 114 mm. X-ray study of the chest revealed bilateral upper-lobe infiltrations, and she was admitted to one of the medical departments of the hospital.

Upon admission, on April 13, she complained of weak- ness and muscular pain. She looked pale, thin and as- thenic. Her mental state was characterized by extreme apathy. Blood tests revealed normal serum creatinine and urea values. The urine contained red and white blood cells. Tomography of the upperlobe infiltrations was

Acta merl. srand. 187

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8 P. Teisberg and E. Enger

thought to exclude tuberculosis and tumour. The tuber- culin reaction was now negative-she had been positive after BCG vaccination as a child.

Her clinical condition was rapidly deteriorating. Be- cause of heavy nausea with vomiting and general weak- ness renal function tests and analysis of blood electro- lytes were repeated primo May. This revealed the follow- ing values: potassium 6.2 mEq/l, serum creatinine 13 mg/100 ml, and urea 273 mg/100 ml. On May 11 she was remitted to the Renal Unit, Department VII.

Treafinenl and course On admission she was anuric with serum creatinine 13.7 mg/100 ml. The haemoglobin content was 8.7 g/100 ml, the haematocrit 27, and the ESR 107 mm. Analysis of the urine revealed protein and blood. Upon microscopic examination red and white blood cells, hyaline, granu- lated and waxy casts were noted.

The clinical picture suggested the diagnosis of Wege- ner’s granulomatosis. Light microscopy and electron mic- roscopy of percutaneous renal biopsy revealed changes in accordance with this diagnosis. Histological examina- tion of biopsy from muscular tissue also suggested Wege- ner’s granulomatosis.

Peritoneal dialysis was started. Simultaneously she re- ceived a combined immunosuppressive regimen with aza- thioprine 2 mg/kg body weight and prednisone 80 mg daily.

Her condition was extremely bad through the first five weeks. Dialysis had to be performed daily. She received several blood transfusions and sufficient calories were provided through a gastric tube. Three weeks after the start of therapy there were signs of azathioprine overdosage. For a period she had extreme leucopenia and thrombocytopenia, and haemoglobin values fell sharply. Because of pneumonia she received massive anti- biotic treatment. After about two weeks the blood values allowed the immunosuppressive regimen to be resumed at reduced dosage.

From the last days of June, or about 7 weeks after the start of therapy, her condition gradually improved. The diuresis which for five weeks had varied between 500 and 700 ml rose, and the renal function improved. On July 1 peritoneal dialysis could be terminated. X-ray of the chest also revealed regression of her upper-lobe infiltrations.

The patient remained in the department until Septem- ber 7. The serum creatinine values stabilized at 2 mg/ 100 ml with creatinine clearance of about 25 ml/min. The protein content of 24-hour specimens of urine fell to about 2 g. The urinary sediment revealed a similar im- provement, but there were still a few cellular elements and granular casts. Nausea and vomiting, probably re- lated to the azathioprine therapy, were noted during a short period. The medication was temporarily reduced and later she has tolerated the same doses as before.

At discharge from the hospital her general condition was good. She had gained 10 kg and was able to do light work. There was no longer secretion from the ear, the facial nerve palsy was less pronounced and the ab- dominal wound had completely healed. X-ray of the chest still showed a small, dense infiltration in the middle of

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the right lung. There were only remnants left of the upper-lobe infiltrations.

Follow-up The immunosuppressive regimen has been continued with azathioprine 100 mg and prednisone 15 mg daily. Be- cause of danger of azathioprine toxicity the blood values have been checked weekly. Every 2-3 months she has been readmitted to the Renal Unit for more complete controls. In May 1969, i.e. one year after her first ad- mission to the Renal Unit, her general condition was very good. Serum creatinine was 1.9 mg/100 ml and creatinine clearance 20 ml/min. Still there was a moderate pro- teinuria, but the sediment only contained a few hyaline casts. X-ray of the chest revealed further regression of the infiltration in her right lung.

COMMENTS Evidence of the pathogenetic significance of im- munological mechanisms in Wegener’s granu- lomatosis has led to therapeutic trial of various immunosuppressive agents.

The value of corticosteroids used alone is dis- puted (2, 5) . In high dosagz they may provide beneficial effects in the early stages of the disease. Renal insufficiency, however, is not affected by this treatment. The corticosteroids can at best lengthen the patient’s life by a few months.

During the last two years there have been sev- eral reports indicating promising results with im- munosuppressive agents, such as chlorambucil, nitrogen mustard and azathioprine (3, 5 , 6, 8, 9). The drugs have mostly been used in combination with corticosteroids. Such combined immunosup- pressive regimens have in a few patients induced lasting remissions with observation periods vary- ing from months to two years. Marked improve- ment of the clinical state with healing of res- piratory tract lesions has been noted. In some of these patients there has been moderate impair- ment of renal function with subsequent improve- ment.

The present patient was in an unusually ad- vanced stage of the disease when treatment was started. A combined regimen of azathioprine and prednisone was used. Azathioprine is currently regarded as the immunosuppressive agent of choice in the group of antimetabolites, alkylating agents and antibiotics which have been used for this purpose. It is probably the most effective and certainly the least toxic of the available drugs in this group (1, 4). There is ample evidence of the anti-inflammatory and immunosuppressive effects

of the corticosteroids. The exact mode of action of these drugs is not known. Azathioprine is thought in some way to inhibit the synthesis of deoxyribonucleic acid or ribonucleic acid or both.

According to the literature non-treated cases of Wegener’s granulomatosis with renal involve- ment end fatally within a few months. The im- munosuppressive rzgimen used in this patient has been able to induce a lasting remission despite the prescnce of advanced renal failure with an oliguric period of several wzeks.

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REFERENCES Aisenberg, A. C.: Drugs employed for the suppres- sion of immunologic responsiveness. New Engl. J. Med. 272: 1114, 1965. Beidelman, B.: Wegener’s granulomatosis. J. Amer. med. Ass. 186: 827, 1963. Bouroncle, B. A., Smith, E. J. & Cuppage, F. E.: Treatment of Wegener’s granulomatosis with Imuran. Amer. J. Med. 42: 314, 1967. Calne, R. Y.: Inhibition of the rejection of renal homografts in dogs by drugs. Ann. roy. Coll. Surg. Engl. 32: 281, 1963. Hollander, D. & Manning, R. T.: The use of alkylat- ing agents in the treatment of Wegener’s granuloma- tosis. Ann. intern. Med. 67: 393, 1967. Kaplan, S. R., Hayslett, J. P. & Calabresi, P.: Treat- ment of advanced Wegener’s granulomatosis with aza- thioprine and duazomycin A. New Engl. J. Med. 278: 239, 1968. Klinger, N.: Grenzformen der Periarteritis nodosa. Frankfurt. Z. Path. 42: 455, 1931. McIlvanie, S. K.: Wegener’s granulomatosis: success- ful treatment with chlorambucil. J. Amer. med. Ass. 197: 130, 1966. Norton, W. L., Suki, W. & Strunk, S.: Combined corticosteroid and azathioprine therapy in two pa- tients with Wegener’s granulomatosis. Arch. intern. Med. 121: 554, 1968. Wegener, F.: Uber generalisierte, septische Gefasser- krankungen. Verh. dtsch. path. Ges. 29: 202, 1936. - Uber eine eigenartige rhinogene Granulomatose mit besonderer Beteiligung des Arterien Systems und der Nieren. Beitr. path. Anat. 102: 36, 1939.

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