Maintaining Remission in a Patient With Vasculitis

Oliver Flossmann; David R.W. Jayne


Nat Clin Pract Rheumatol. 2008;4(9):499-504. 

In This Article

Summary and The Case


Background: A 40-year-old man was referred to a specialist vasculitis center 4 years after being diagnosed with Wegener's granulomatosis. At the time of diagnosis he had presented with skin, ear, nose and throat involvement, pulmonary hemorrhage, and microscopic hematuria. Remission was achieved with plasma exchange and with daily oral prednisolone and cyclophosphamide. The patient was switched to maintenance treatment with azathioprine and prednisolone but suffered a relapse shortly afterwards. Further treatment with cyclophosphamide achieved a second remission, but the patient relapsed again despite remission-maintaining treatment with mycophenolate mofetil.
Investigations: Physical examination, laboratory testing, serological testing, culture of eye swabs and sputum, chest X-ray, chest CT scan, head MRI scan, bronchoscopy and bronchoalveolar lavage, and consultation with ophthalmological and otorhinolaryngological specialists.
Diagnosis: Refractory Wegener's granulomatosis with involvement of the eyes, upper and lower respiratory tracts, and kidneys.
Management: Disease activity was controlled following treatment with deoxyspergualin and oral steroids in addition to aggressive management of intercurrent infections with repeated courses of oral and intravenous antibiotics. Relapses that occurred when deoxyspergualin was discontinued were treated with repeated courses of deoxyspergualin or with pulsed intravenous cyclophosphamide. Remission was achieved with rituximab. Pulmonary disease was closely monitored with repeated bronchoscopy.

The Case

A 40-year-old man had previously presented to his local hospital with a 6-month history of arthralgia, malaise, pyrexia, sinus pain and hemorrhagic nasal discharge. Examination revealed a purpuric skin rash, hematuria and proteinuria. Serum level of creatinine was normal at 94 µmol/l. Skin biopsy showed a necrotizing vasculitis predominantly involving small blood vessels. A diagnosis of Wegener's granulomatosis was made and treatment with prednisolone (60 mg daily) and azathioprine (200 mg daily) was started. A planned renal biopsy was not performed because the patient became severely ill due to lung hemorrhage within 7 days of starting treatment. Therapy with pulsed intravenous methyl prednisolone, plasma exchange and oral cyclophosphamide (300 mg daily) was started. Tests for anti-neutrophil cytoplasm antibody (ANCA) revealed high levels of cytoplasmic-staining ANCA and of antiproteinase 3 antibody (PR3)-ANCA.

The patient's clinical condition stabilized and he was discharged after 16 days. Three months later, cyclophosphamide was substituted with azathioprine (200 mg daily); prednisolone was continued at 10 mg daily. At this point the patient's condition was much improved, with only mild persistent nasal symptoms and a normal urine dipstick analysis. A minor relapse 4 months later affecting his joints and nose was successfully treated with an increase in azathioprine to 250 mg daily and prednisolone to 20 mg daily. At 1 year after diagnosis the patient was symptomatically stable with only minor nasal symptoms. Renal function remained normal, C-reactive protein (CRP) was marginally elevated and PR3-ANCA remained strongly positive (>100 U/ml; normal value <6 U/ml).

A second relapse had occurred at 23 months after the initial presentation, during which the patient had headaches, deafness and CRP level of 70 mg/dl (normal <6 mg/dl) while receiving azathioprine 150 mg daily and prednisolone 7 mg daily. Although he responded transiently to an increase in prednisolone dose to 15 mg daily, by 29 months the patient became breathless and had recurrent hemoptysis, and a chest X-ray demonstrated pulmonary consolidation and cavitation. After an infective cause of his symptoms was excluded, he received a second course of oral cyclophosphamide 150 mg daily for 3 months and a tapering dose of oral prednisolone starting at 60 mg daily. This treatment resulted in symptomatic and radiological improvement, and levels of CRP fell to 15 mg/dl and PR3-ANCA to 7 U/ml. Prednisolone dose was decreased to 10 mg daily 5 months after starting the second course of cyclophosphamide, and mycophenolate mofetil (MMF) 2 g daily was started to maintain remission. Within 4 months of initiating this regimen, levels of CRP and PR3-ANCA had risen again and did not fall following increases in MMF dose to 3 g daily and in prednisolone dose to 30 mg daily.

The patient was referred to a specialist vasculitis center 4 years after being diagnosed with Wegener's granulomatosis. He had ongoing epistaxis, nasal crusting, bilateral hearing loss requiring hearing aids, chronic coughing, wheezing and rib pain. He appeared cushingoid, his left lung base was dull to percussion, and auscultation of the chest revealed a fixed expiratory wheeze. Urine tests showed microscopic hematuria and proteinuria. Results of the blood tests undertaken are summarized in Table 1 . A chest X-ray showed a large fluid-filled cavity in the left midzone and shadowing in the left lower zone (Figure 1a). Bronchoscopy showed granulomatous lesions in the lower trachea and almost complete obstruction of the left main bronchus. Ophthalmological investigation revealed severe scarring and ulceration of the tarsal conjunctivae with purulent discharge. At the time of this presentation the patient was receiving immunosuppression with MMF 3 g daily and prednisolone 17.5 mg daily.

Figure 1.

Serial chest X-rays and a CT scan of a patient with Wegener's granulomatosis. (A) Chest X-ray taken at the time of presentation to a specialist vasculitis center, 4 years after diagnosis, showing a large fluid-filled cavity in the left midzone and shadowing in the left lower zone. (B) Chest X-ray taken after six 28-day cycles of treatment with deoxyspergualin. The appearance of the left midzone cavity is markedly improved. (C) Chest X-ray taken 1 month after the start of treatment with mycophenolate mofetil, in which the appearance of the left midzone cavity has worsened. (D) CT scan of the patient's chest taken 10 months after the start of repeat treatment with deoxyspergualin. The large left cavity present on the earlier chest X-rays is now replaced by scarring. Also present, however, are a small cavity and a nodule in the right lower and middle lobe, which are not obvious on the chest X-rays taken before and after deoxyspergualin treatment (i.e. Figure 1c,e). This image demonstrates the superior sensitivity of CT scans, in particular for smaller lesions, compared with X-rays. (E) Chest X-ray taken 2 months after the CT scan, showing that the midzone cavity is almost completely resolved with only residual scarring. Abbreviations: A, anterior; L, left; P, posterior; R, right.

The patient was diagnosed with refractory Wegener's granulomatosis that involved the eyes, upper and lower airways, and kidneys. MMF was discontinued and the patient was enrolled in a trial of deoxyspergualin, a novel immunosuppressant. He received a series of six 28-day cycles, which comprised subcutaneous administration of deoxyspergualin 0.5 mg/kg daily for up to 21 days (stopped earlier if the white blood cell count dropped below 4 × 109/l) and a washout period of 7 days between cycles, in addition to a tapering dose of prednisolone.

The patient suffered recurrent episodes of worsening chest symptoms, with purulent discharge and pyrexia that were resistant to oral antibiotics and were finally controlled by a 4-day course of intravenous cefotaxime. After six 28-day cycles of deoxyspergualin his clinical condition had markedly improved (Figure 1b). Prednisolone administration was reduced to 10 mg daily. MMF 3 g daily was restarted, but within 4 weeks the patient's condition deteriorated and he developed an enlarging lung cavity (Figure 1c) and recurrent tarsal conjunctivitis. MMF was discontinued and remission was obtained and maintained for a further 16 months with deoxyspergualin (Figure 1d,e). As a result of supply problems, treatment with deoxyspergualin was then interrupted for 4 weeks, which led to a relapse with endobronchial inflammation. The endobronchial lesions improved after a further 4 months of treatment with pulsed intravenous cyclophosphamide. Deoxyspergualin was subsequently resumed and produced further improvement and remission after 3 months, but, as a future supply of deoxyspergualin could not be guaranteed, rituximab (1 g on two occasions, 2 weeks apart) was administered to maintain the remission state. Depletion of circulating B cells was achieved with rituximab and 6 months later the patient was well with no active disease. Remission was maintained with prednisolone 6 mg daily and no further immunosuppressives. We plan to repeat single rituximab (1 g) infusions every 6 months irrespective of levels of circulating B cells in order to control future disease, in addition to continuing the administration of low-dose prednisolone. The overall disease course and treatment of this patient are summarized in Figure 2.

Figure 2.

The course of disease activity in a patient with Wegener's granulomatosis and the treatment decisions taken. The top panel indicates disease activity, as measured by BVAS2003. The bottom panel indicates daily prednisolone dose. Abbreviations: AZA = azathioprine; BVAS2003 = Birmingham Vasculitis Activity Score 2003; CYC = cyclophosphamide; DSG = deoxyspergualin; MMF = mycophenolate mofetil; RIT = rituximab.


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