The treatment of Wegener's granulomatosis with glucocorticoids and methotrexate.

OBJECTIVE. To identify alternatives to daily low-dose cyclophosphamide (CYC) in the treatment of Wegener's granulomatosis (WG). METHODS. An open-label pilot study of weekly low-dose methotrexate (MTX) plus glucocorticoids (GC) for treatment of patients with WG was performed. Twenty-nine patients who did not have immediately life-threatening disease were included. Outcome was determined by clinical characteristics, pathologic findings, course of illness, laboratory and radiographic findings, and successful withdrawal of GC therapy. RESULTS. Weekly administration of MTX (at a mean stable dosage of 20 mg) and GC resulted in marked improvement in 76% of the 29 patients. Remission was achieved in 69% of the patients, 7% improved but had intermittent smoldering disease that precluded total withdrawal of GC, and 17% had progressive disease within 2-6 months of starting the study treatment. Two patients who initially achieved remission later had relapses after GC was discontinued. Of those who remain in remission (mean followup time 14.5 months), 72% have not required GC for a mean period of 10 months. CONCLUSION. Although standard therapy for WG (daily CYC and GC) has dramatically improved outcome in this often-fatal disease, treatment morbidity has led to attempts to identify effective interventions that have less toxicity. Weekly low-dose MTX was shown in this study to be a feasible alternative to CYC in patients whose illness was not immediately life-threatening or in whom prior CYC treatment was ineffective or produced serious toxicity. Although these results are preliminary, they are encouraging and justify further studies in which MTX, CYC, and other alternative therapeutic approaches are compared concurrently.     

The treatment of wegener's granulomatosis with glucocorticoids and methotrexate

Objective. To identify alternatives to daily low-dose cyclophosphamide (CYC) in the treatment of Wegener's granulomatosis (WG). Methods. An open-label pilot study of weekly low-dose methotrexate (MTX) plus glucocorticoids (GC) for treatment of patients with WG was performed. Twenty-nine patients who did not have immediately life-threatening disease were included. Outcome was determined by clinical characteristics, pathologic findings, course of illness, laboratory and radiographic findings, and successful withdrawal of GC therapy. Results. Weekly administration of MTX (at a mean stable dosage of 20 mg) and GC resulted in marked improvement in 76% of the 29 patients. Remission was achieved in 69% of the patients, 7% improved but had intermittent smoldering disease that precluded total withdrawal of GC, and 17% had progressive disease within 2–6 months of starting the study treatment. Two patients who initially achieved remission later had relapses after GC was discontinued. Of those who remain in remission (mean followup time 14.5 months), 72% have not required GC for a mean period of 10 months. Conclusion. Although standard therapy for WG (daily CYC and GC) has dramatically improved outcome in this often-fatal disease, treatment morbidity has led to attempts to identify effective interventions that have less toxicity. Weekly low-dose MTX was shown in this study to be a feasible alternative to CYC in patients whose illness was not immediately life-threatening or in whom prior CYC treatment was ineffective or produced serious toxicity. Although these results are preliminary, they are encouraging and justify further studies in which MTX, CYC, and other alternative therapeutic approaches are compared concurrently.     

Longterm outcome of Wegener's granulomatosis in patients with renal disease requiring dialysis

OBJECTIVE: It is known that renal failure is a poor prognostic marker for survival in Wegener's granulomatosis (WG). We investigated the longterm outcome of patients with WG who have severe renal disease requiring dialysis. METHODS: We performed a retrospective analysis of 104 patients with WG followed at our institution between 1982 and 1997. Twenty-three patients who required dialysis were studied in detail to determine outcomes and factors that influenced survival and restoration of renal function. RESULTS: Of 23 dialysis dependent patients with WG, 11 died (Group 1). 7 either remained dialysis dependent or received successful renal transplants (Group 2), and 5 substantially recovered renal function (Group 3). Mean serum creatinine at the end of a mean followup period of 38.4 months for Group 3 was 1.8 mg/dl. There was no apparent difference between groups in regard to disease profile, e.g., distribution of organ involvement or serum creatinine when renal impairment was first recognized (mean serum creatinine for groups: 1: 3.0 mg/dl; 2: 5.6 mg/dl; 3: 5.5 mg/dl) and peak serum creatinine prior to dialysis (means for groups: 1: 9.5 mg/dl; 2: 10.5 mg/dl; 3: 9.6 mg/dl). Infection secondary to immunosuppression was the leading cause of death in Group I patients. CONCLUSION: Because the clinical profile and degree of renal failure, as judged by serum creatinine, did not differ among patients who did or did not regain dialysis independent renal function, we recommend aggressive immunosuppressive therapy in all cases of active WG with acute rapidly worsening renal failure, regardless of the severity of renal impairment.     

Wegener's granulomatosis. Long-term followup of patients treated with cyclophosphamide.

Ten patients with Wegener's granulomatosis were treated with cyclophosphamide and followed for periods up to 7 years. In all cases cyclophosphamide induced complete remissions. The mean duration of remission (to date) was 38 months. Six patients have been in remission for a mean of 46 months after cyclophosphamide was discontinued; 2 have been disease-free for 7 years. Of the 10 patients treated, only 1 relapsed and she responded to a second course of cyclophosphamide. These results indicate that cyclophosphamide is the drug of choice in Wegener's granulomatosis. The long-term effectiveness of this drug suggests that it may induce permanent remissions in certain patients with Wegener's granulomatosis.     

High rate of renal relapse in 71 patients with Wegener's granulomatosis under maintenance of remission with low-dose methotrexate

OBJECTIVE: To examine the long-term efficacy of low-dose intravenous methotrexate (MTX) with and without concomitant glucocorticoids (GC) for remission maintenance in patients with generalized Wegener's granulomatosis (WG) in an open-label, prospective, standardized trial.METHODS: After induction of remission by cyclophosphamide and GC, 71 patients (41 males, 30 female) with initially generalized WG received low-dose methotrexate at 0.3 mg/kg body weight once weekly. At study-start 55 of 71 (77.5%) patients were on low-dose GC (mean 5.9 mg/day) which was tapered during the study. All patients underwent interdisciplinary staging at 3-month (and later at 6-month) intervals to assess disease activity and extent as well as side effects. End points were the first relapse or the end of study (January 2001).RESULTS: Within a mean followup period of 25.2 months, 26 patients (36.6%) experienced a relapse after a mean of 19.4 months. Seventeen (65.4%) of these 26 patients had terminated GC therapy at the time of relapse. There was no difference in relapse rates among patients with and without concomitant GC at study start. Relapses occurred mainly in the initially involved organ systems, preferentially in the ear, nose and throat tract in 18 of 26 patients and the kidney in 16 of 26 patients. One renal relapse presented as rapid, progressive glomerulonephritis with lethal outcome. Further, 14 relapses were accompanied by a significant rise in creatinine values. In 15/26 patients the relapse was paralleled or preceded by a significant rise of antineutrophil cytoplasmic antibody titer. Two patients ceased MTX prematurely because of persistent leukopenia.CONCLUSION: Weekly MTX is a well tolerated therapy for long-term maintenance of remission. However, one-third of the patients relapsed during ongoing MTX treatment, irrespective of whether they were still receiving GC. Because more than half of the relapses affected the kidney, close monitoring is indispensable.     

Effects of glucocorticoids on weight change during the treatment of Wegener's granulomatosis

OBJECTIVE: Weight gain is a side effect of glucocorticoid (GC) use, but the natural history and health implications of changes in weight that occur during the treatment of inflammatory disease are not understood. METHODS: We evaluated data from the Wegener's Granulomatosis Etanercept Trial. Patients were categorized according to clinical outcome at 1 year: remission (no disease flares), single flare, or multiple flares. Risk factors for gaining > or =10 kg were examined in multivariate models. RESULTS: Weights at baseline and 1 year were available for 157 (93%) of the 168 patients analyzed. During year 1, the mean cumulative prednisone dosage in the multiple flares subgroup was 7.9 gm, compared with 6.0 gm and 3.9 gm in the single flare and remission subgroups, respectively (P < 0.001). Patients in these subgroups gained an average of 2.6 kg, 4.1 kg, and 5.8 kg, respectively (P = 0.005). Weight gain did not correlate with cumulative GC dose (R = 0.10, P = 0.25). Thirty-five patients (22.3%) gained and maintained > or =10 kg in the first year. New diagnosis of Wegener's granulomatosis at baseline was an independent predictor of gaining > or =10 kg at 1 year (odds ratio 19.7, 95% confidence interval 2.4-162.6, P = 0.006). Among the 78 patients in the remission subgroup, 40 sustained remissions through the 2-year time point. For these 40 patients, the mean weight gained at year 1 did not regress by the end of year 2, despite the absence of continued GC use. CONCLUSION: Disease control was associated with lower cumulative GC doses but greater weight gain. More than one-fifth of patients gained >10 kg in the first year of treatment. The quantity of weight gained by patients during treatment has potential future health implications.     

Clinical outcome of patients with Wegener's granulomatosis treated with plasma exchange

We report the clinical course of 29 patients with Wegener's granulomatosis (WG) treated with plasma exchange (PE) in Norway in the period from 1988 to 1999. Median follow-up was 41.5 months. The mean number of exchanges was 8.5 +/- 5.8 (range 2-32). Median serum creatinine concentration was 400 micromol/l (range 90-1,356) and 17 patients were dialysis dependent at presentation. Two- and five-year patient survival was 75 and 71%, respectively, and renal (ESRD-free) survival was 74 and 54%, respectively. Seven (50%) of the 14 patients alive in the dialysis group had discontinued dialysis within the first month, and 6 (50%) of 12 patients alive at follow-up had independent renal function. No patients, however, had normal serum creatinine concentration. Median time until development of ESRD for patients presenting with a need for dialysis was approximately 32 months. The development of ESRD in 79 patients treated with immunosuppression alone was significantly lower, but when adjusted for serum creatinine there was no difference between patients treated with or without PE. Although a considerable fraction of patients with WG and severe renal involvement regain independent renal function, few will have normal serum creatinine concentration at follow-up, despite the addition of PE as adjunctive therapy.     

Wegener's granulomatosis in India: clinical features, treatment and outcome of twenty-five patients

OBJECTIVE: To report our clinical experience on Wegener's granulomatosis (WG). METHODS: A retrospective review of case records of all patients with WG in our Rheumatology Clinic during the period July 1988 to June 2000 was carried out and the details of demography, clinical and laboratory data, treatment and outcome were obtained and analysed. RESULTS: Twenty-five patients (16 females and 9 males) were found eligible for inclusion in the study. The mean age and duration of symptoms at presentation were 33.5 years and 5.5 months, respectively. Two patients had limited WG. Twenty-two patients with generalized WG were treated with standard regimen comprising oral prednisolone (1 mg/kg/day) and oral cyclophosphamide (2 mg/kg/day). Cyclophosphamide was continued for at least one year after the patient attained remission. One patient was treated with intravenous cyclophosphamide regimen. The two patients with limited WG were treated with oral prednisolone and methotrexate (10-12.5 mg as a single dose per week). Remission was achieved in 24 patients after a median time of six months. The median follow-up of patients was five years (range 4 months-11 years). Five patients were lost to follow-up. Eight patients suffered a relapse. The mean time for relapse was 34 months after the initial remission. Seven out of eight patients remitted again after reinstitution of the initial induction regimen. One patient died of diffuse pulmonary haemorrhage despite early institution of therapy. CONCLUSION: WG is being increasingly diagnosed in India now because of greater awareness and diagnostic aids. Although remissions are easy to achieve, relapses continue to pose a challenge to the treating physician.     

A staged approach to the treatment of Wegener's granulomatosis: induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance

OBJECTIVE: To determine the efficacy of a daily cyclophosphamide (CYC) and glucocorticoid induction and methotrexate (MTX) remission-maintenance regimen for the treatment of Wegener's granulomatosis (WG). METHODS: An open-label, prospective, standardized trial for the treatment of WG was performed using CYC and glucocorticoids for remission induction and MTX for remission maintenance. Thirty-one patients were enrolled in this study. Outcome was assessed using predetermined definitions based on clinical characteristics and pathologic, laboratory, and radiographic findings. RESULTS: The use of CYC and glucocorticoids for remission induction and MTX for remission maintenance resulted in disease remission for all 31 patients. The median time to remission was 3 months and the median time to discontinuation of glucocorticoids was 8 months. No patients have died, and 5 patients (16%) have had disease relapses at a median of 13 months after achieving remission. Only 2 patients (6%) have had to withdraw from the trial as a result of medication toxicity. CONCLUSION: The use of CYC and glucocorticoids for remission induction and MTX for remission maintenance was shown by this study to be an acceptable alternative therapy for patients with active WG, including those with severe disease at onset.     

High rate of renal relapse in 71 patients with Wegener's granulomatosis under maintenance of remission with low‐dose methotrexate

Objective

To examine the long‐term efficacy of low‐dose intravenous methotrexate (MTX) with and without concomitant glucocorticoids (GC) for remission maintenance in patients with generalized Wegener's granulomatosis (WG) in an open‐label, prospective, standardized trial.

Methods

After induction of remission by cyclophosphamide and GC, 71 patients (41 males, 30 female) with initially generalized WG received low‐dose methotrexate at 0.3 mg/kg body weight once weekly. At study‐start 55 of 71 (77.5%) patients were on low‐dose GC (mean 5.9 mg/day) which was tapered during the study. All patients underwent interdisciplinary staging at 3‐month (and later at 6‐month) intervals to assess disease activity and extent as well as side effects. End points were the first relapse or the end of study (January 2001).

Results

Within a mean followup period of 25.2 months, 26 patients (36.6%) experienced a relapse after a mean of 19.4 months. Seventeen (65.4%) of these 26 patients had terminated GC therapy at the time of relapse. There was no difference in relapse rates among patients with and without concomitant GC at study start. Relapses occurred mainly in the initially involved organ systems, preferentially in the ear, nose and throat tract in 18 of 26 patients and the kidney in 16 of 26 patients. One renal relapse presented as rapid, progressive glomerulonephritis with lethal outcome. Further, 14 relapses were accompanied by a significant rise in creatinine values. In 15/26 patients the relapse was paralleled or preceded by a significant rise of antineutrophil cytoplasmic antibody titer. Two patients ceased MTX prematurely because of persistent leukopenia.

Conclusion

Weekly MTX is a well tolerated therapy for long‐term maintenance of remission. However, one‐third of the patients relapsed during ongoing MTX treatment, irrespective of whether they were still receiving GC. Because more than half of the relapses affected the kidney, close monitoring is indispensable.

     

Exhaled nitric oxide in patients with Wegener's granulomatosis.

In Wegener's granulomatosis (WG), a pathogenic role of infections, in particular of a chronic colonization of the nasal mucosa with Staphylococcus aureus, has been postulated. Nitric oxide (NO), which is thought to play a role in primary host defence and inflammation, is produced endogenously within the respiratory tract, mainly from the paranasal sinuses. In order to further characterize its role in WG, nasal and pulmonary NO excretion in WG patients in comparison to healthy volunteers was measured. Seventeen patients with WG were included in the study. Five patients had active disease (bloody rhinitis with ulceration and crusting) and immunosuppressive therapy (IST), and 12 were in remission (six with, and six without, IST). S. aureus was found in the swabs of all patients with active WG and in three patients in remission. NO was measured in exhaled gas using a chemiluminescence analyser. The NO excretion rate in nasally sampled gas was significantly reduced (p<0.05) in patients with active WG ((mean+/-SD)102+/-100 nL x min(-1)) compared to healthy controls (299+/-13 nL x min(-1)), and patients in remission (281+/-86 nL x min(-1) with IST, 280+/-133 nL x min(-1) without IST). Pulmonary NO excretion in active or nonactive WG patients did not significantly differ from that of healthy volunteers (48+/-21 nL x min(-1)). These results demonstrate a reduced nasal NO excretion in active Wegener's granulomatosis. This may be caused by destruction and/or functional impairment of sinus epithelium. The reduced NO concentration may well compromise host defence in the upper airways, thus contributing to colonization with Staphylococcus aureus and further promoting Wegener's granulomatosis.     

Periglomerular granulomatosis. A limited form of Wegener's granulomatosis with exclusive renal involvement?

Three episodes of acute renal failure, all of them requiring hemodialysis, were observed in two patients. The renal biopsy specimens showed a massive periglomerular granulomatosis with crescentic glomerulonephritis. With cyclophosphamide therapy, a dramatic improvement in renal function was observed in both patients. Although the histologic findings and the response to cyclophosphamide therapy were characteristic of Wegener's granulomatosis, there was no evidence of respiratory involvement or extrarenal manifestations throughout the patients' clinical course. We think that these cases could represent limited forms of Wegener's granulomatosis with exclusive renal involvement.     

Predicting outcome and survival in patients with Wegener's granulomatosis treated on the intensive care unit

OBJECTIVE: This study was designed to search for risk factors predicting mortality of patients with Wegener's granulomatosis (WG) treated on the intensive care unit (ICU). METHODS: Seventeen patients admitted to the ICU of an University Hospital for an acute illness related to WG were analysed retrospectively over 4 years. A variety of clinical and laboratory variables were recorded. Contingency table analyses, univariate logistic regression, and discriminate analysis were performed to determine which factors influenced a negative outcome. RESULTS: Reasons for ICU admission were respiratory failure (n = 10), severe haemoptysis (n = 13), sepsis (n = 9), acute renal failure (n = 6), and gastrointestinal bleeding (n = 1). Patients were treated for a median of 6 days (range 4-121 days). During the stay in the ICU, five patients died within 24-121 days (overall mortality 29.4%). Causes of death were cerebral haemorrhage (n = 2), pulmonary embolism (n = 1), and sepsis (n = 2). Significantly associated with death were: Acute Physiology and Chronic Health Evaluation II (APACHE II) score>24 [p = 0.004, odds ratio (OR) 0.568, 95% confidence interval (CI) 0.327-0.989], period of time in the ICU>10 days (p = 0.001, OR 0.795, 95% CI 0.589-1.072), and treatment with cyclophosphamide during the stay in the ICU (p = 0.013, OR 0.799, 95% CI 0.651-0.980). No association was found for higher age, C-reactive protein (CRP), pulmonary involvement, serum creatinine, and requirement of haemodialysis. CONCLUSIONS: The prognosis for WG patients in the ICU is serious, but the majority can survive. To achieve a more favourable outcome, patients should stay in the ICU for as short a time as possible. The occurrence of renal failure did not influence the outcome in our patients.     

Accelerated atherosclerosis in patients with Wegener's granulomatosis

BACKGROUND: Several autoimmune disorders are complicated by excess cardiovascular disease. In addition to traditional risk factors, non-traditional risk factors such as endothelial activation and excessive vascular remodelling might be determinants of the progression of atherosclerosis in patients with an autoimmune disease. OBJECTIVE: To evaluate whether patients with Wegener's granulomatosis (WG) have an increased prevalence of atherosclerosis and to determine predisposing factors. METHODS: 29 WG patients (19 men; mean (SD) age, 53 (14) years) with inactive disease and 26 controls (16 men; age 53 (15) years) were studied. Common carotid intima-media thickness (IMT) was measured by ultrasound. In all individuals traditional risk factors for cardiovascular disease were determined. High sensitivity C reactive protein (hsCRP) was measured. Endothelial activation was assessed by measuring thrombomodulin, vascular cell adhesion molecule-1, and von Willebrand factor. As a marker of vascular remodelling matrix metalloproteinases (MMP-3 and MMP-9) and TIMP-1 were measured. RESULTS: IMT was increased in WG patients compared with controls (p<0.05). No differences in traditional risk factors and endothelial activation markers between patients and controls were found. Levels of hsCRP, MMPs, and TIMP-1 were increased in WG patients (p<0.05). CONCLUSIONS: Increased IMT found in WG patients cannot be explained by an increased prevalence of traditional risk factors. Although endothelial activation markers in WG patients with inactive disease were not increased, the raised levels of hsCRP, MMPs, and TIMP-1 suggest that enhanced inflammation and excessive vascular remodelling are contributing factors in the development of accelerated atherosclerosis in WG.     

Cardiac involvement in patients with Wegener's granulomatosis

Wegener's granulomatosis (WG) is a systemic necrotizing vasculitis, which could potentially affect any organ system. However, there have only been a few reports on cardiac involvement. We described the echocardiographic findings in nine patients affected by WG. A complete M-mode, two-dimensional, Doppler and color-Doppler transthoracic echocardiogram was performed in nine patients (seven females and two males) affected by WG. In each patient, cardiac abnormality, for example, valvular damage, left ventricular global systolic dysfunction, or pericardial effusion, was detected. In particular, heart valve disease was found in eight patients, and in three cases, aortic valve insufficiency, which was severe enough to require surgical valve replacement, was observed. Cardiac involvement in patients with WG is common. In particular, there is a high frequency of aortic valve abnormalities. Thus, an echocardiographic study should be routinely performed. Received: 21 October 1999 / Accepted: 28 April 2000     

Wegener's granulomatosis in patients with rheumatoid arthritis

OBJECTIVE: To describe 2 cases of coexisting rheumatoid arthritis (RA) and Wegener's granulomatosis (WG), and to summarize the clinical and serological data for all 6 patients reported in the English literature since 1966. METHODS: Medline review over a 35-year period (1966-2002) revealed 4 reported cases of RA associated with WG. Patients were diagnosed based on symptoms, radiographic changes, bronchoalveolar lavage fluid analysis, hematuria, serology, and biopsy. We describe 2 additional cases of WG developing in Caucasian women with RA. These are the first reported patients to possess positive antineutrophil cytoplasmic antibodies (ANCA) and autoantibodies to proteinase 3 (PR3). RESULTS: All 6 cases of coexisting RA and WG were female. The diagnosis of RA preceded WG diagnosis in all cases; mean age at RA onset was 43.7 +/- 15.0 years, duration of RA prior to WG diagnosis 7.9 +/- 9.1 years. Clinical findings included erosive articular disease on radiographs (n = 4; 67%), positive rheumatoid factor (n = 6; 100%), upper respiratory involvement (n = 5; 83%), lower respiratory signs (n = 4; 67%), renal involvement (n = 2; 33%), and positive ANCA (n = 2/3; 67%). Five patients were treated with corticosteroids and cyclophosphamide, with clinical improvement. CONCLUSION: Although rare, WG may develop in patients with preexisting RA and may present with end-organ involvement.     

Monocyte activation in patients with Wegener's granulomatosis

OBJECTIVE: Wegener's granulomatosis (WG) is an inflammatory disorder characterised by granulomatous inflammation, vasculitis, and necrotising vasculitis and is strongly associated with anti-neutrophil cytoplasmic antibodies (ANCA). Activated monocytes/macrophages are present in renal biopsy specimens and participate in granuloma formation by synthesising and secreting a variety of chemoattractants, growth factors, and cytokines. In view of these findings, in vivo monocyte activation was evaluated in patients with WG and the findings related to parameters of clinical disease activity. METHODS: Monocyte activation was analysed by measuring plasma concentrations of soluble products of monocyte activation, that is neopterin and interleukin 6 (IL6), by ELISA, and by quantitating the surface expression of activation markers on circulating monocytes by flow cytometry. RESULTS: Twenty-four patients with active WG were included in this study. Ten of these patients were also analysed at the time of remission. Twelve patients with sepsis served as positive controls, and 10 healthy volunteers as negative controls for monocyte activation. Patients with active disease had increased monocyte activation compared with healthy controls as shown by increased concentrations of neopterin (p < 0.0001) and increased surface expression of CD11b (p < 0.05) and CD64 (p < 0.05). In those patients with increased concentrations of IL6 during active disease plasma concentrations of IL6 decreased during follow up when patients went into remission (p < 0.0001). In addition, neopterin (r = 0.37, r = 0.44), IL6 (r = 0.37, r = 0.60) and CD63 expression (r = 0.39, r = 0.45) correlated significantly with disease activity as measured by the Birmingham Vasculitis Activity Score and C reactive protein values, respectively. Compared with patients with sepsis, all markers of monocyte activation in patients with vasculitis were lower. CONCLUSION: It is concluded that disease activity in WG correlates with the extent of activation of monocytes, compatible with their role in the pathophysiology of this disease.