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Initial immunosuppressive therapy in granulomatosis with polyangiitis (Wegener's) and microscopic polyangiitis
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2012. | This topic last updated: Mar 28, 2012.

NEW TERMINOLOGY — In January 2011, the Boards of Directors of the American College of Rheumatology, the American Society of Nephrology, and the European League Against Rheumatism recommended that the name Wegener’s granulomatosis be changed to granulomatosis with polyangiitis (Wegener’s), abbreviated as GPA [1-3]. This change reflects a plan to gradually shift from honorific eponyms to a disease-descriptive or etiology-based nomenclature. The parenthetic reference to Wegener’s will be phased out after several years as the new name becomes more widely known.

INTRODUCTION — Granulomatosis with polyangiitis (Wegener’s), which can be abbreviated as GPA, and microscopic polyangiitis (MPA) are related systemic vasculitides. Both are associated with antineutrophil cytoplasmic antibodies (ANCA), have similar features on renal histology (eg, a focal necrotizing, pauci-immune glomerulonephritis), and have similar outcomes. There are, however, several differences between these disorders. (See "Clinical manifestations and diagnosis of granulomatosis with polyangiitis (Wegener's) and microscopic polyangiitis", section on 'Clinical presentation'.)

Therapy of GPA and MPA has two components: induction of remission with initial immunosuppressive therapy, and maintenance immunosuppressive therapy for a variable period to prevent relapse.

The initial immunosuppressive therapy of GPA and MPA will be reviewed here. Maintenance immunosuppressive therapy following induction of remission, the treatment of cyclophosphamide resistant or relapsing disease, the clinical manifestations and diagnosis of these disorders, and patient and renal outcomes are discussed elsewhere. (See "Maintenance immunosuppressive therapy in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis" and "Treatment of cyclophosphamide-resistant granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis" and "Relapsing disease in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis" and "Clinical manifestations and diagnosis of granulomatosis with polyangiitis (Wegener's) and microscopic polyangiitis" and "Patient and renal outcomes in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis".)

GENERAL PRINCIPLES

Assessment of disease activity — A variety of methods have been used to assess disease activity in patients with granulomatosis with polyangiitis (Wegener’s), abbreviated as GPA, or microscopic polyangiitis (MPA). As an example, the Birmingham Vasculitis Activity Score (BVAS) has been applied to patients with GPA (BVAS/GPA). The score includes both general symptoms (arthralgia, arthritis, and fever) and involvement of eight major organ systems. At each site, persistent symptoms or manifestations (eg, hematuria) are given one point and new or worse symptoms are given two points. (See "Overview of the management of the vasculitides in adults", section on 'Patient monitoring'.)

The BVAS/GPA score ranges from 0 (complete remission) to a maximum of 68. Major manifestations are defined as those that pose an immediate threat to the patient's life or to the function of a vital organ. These include gangrene, alveolar hemorrhage, respiratory failure, nervous system involvement, sensorineural deafness, mesenteric ischemia, scleritis, retinal exudates or hemorrhage, red blood cell casts, and a rise in serum creatinine.

Immunosuppressive therapy is indicated in all patients with active GPA or MPA. Even patients with advanced renal disease at presentation are highly likely to benefit. In one report, for example, remission was induced in 72 percent of 240 patients with an estimated glomerular filtration rate (eGFR) ≤30 mL/min, 68 percent of 188 patients with an eGFR ≤20 mL/min, and 57 percent of 96 patients with an eGFR ≤10 mL/min [4].

Definition of complete remission — Induction of complete remission is the goal of immunosuppressive therapy in GPA or MPA and is defined as the absence of active disease. A number of definitions of complete remission have been used and the definitions have evolved over time.

In the 1992 National Institutes of Health study demonstrating the efficacy of cyclophosphamide, the criteria for complete remission included absence of systemic inflammatory disease such as serositis and fever, complete resolution of pulmonary infiltrates or stable scarring without signs of active inflammation, and an inactive urine sediment with stabilization of or improvement in renal function [5].

Similar criteria were used in a 1996 report from the University of North Carolina [6]. Complete remission was defined as stabilization of or reduction in the serum creatinine and resolution of extrarenal manifestations. Persistent proteinuria was not considered a sign of persistent disease activity.

The BVAS/GPA score described in the preceding section is more comprehensive, as it includes both systemic manifestations and involvement of eight organ systems [7,8]. Complete remission is defined as a score of 0. In terms of renal involvement, the BVAS/GPA score uses hematuria or red cell casts as a sign of active disease. Red cell casts are not present in some patients with hematuria due to vasculitis and there can be many false positive and false negative results if read by inexperienced observers.

Renal remission — If there is no active renal inflammation, then hematuria and, if present, red cell casts should remit, which is defined as 0 to 3 red cells per high power field. However, there are two other potential causes of hematuria that can occur in patients with GPA or MPA that are unrelated to active renal inflammation:

  • Persistent hematuria at the time of apparent remission may reflect cyclophosphamide-induced cystitis. The red cells in this setting are typically isomorphic (normomorphic), not dysmorphic as with glomerular hematuria (picture 1A-B) and cystoscopy usually shows signs of bladder injury (70 percent in one series) [9]. (See "Etiology and evaluation of hematuria in adults", section on 'Red cell morphology'.)

    In addition, the hematuria due to bladder injury should resolve within three to four weeks after the last cyclophosphamide dose. Persistent monomorphic hematuria raises the possibility of cyclophosphamide-induced bladder cancer, which is not typically seen with the usually short duration of cyclophosphamide therapy now used in patients with GPA or MPA [9]. (See "Epidemiology and etiology of urothelial (transitional cell) carcinoma of the bladder", section on 'Cyclophosphamide'.)
  • Premenopausal women often have blood in the urine during menses due to contamination from menstrual bleeding. Short of bladder catheterization, the etiology of hematuria is best determined by repeat urinalysis after the cessation of menses. This is not a common issue in patients with GPA or MPA, since the mean age is over 50 years and most affected women are postmenopausal.

Active disease versus irreversible injury — Complete remission does NOT mean that all parameters have to return to baseline [5]. Many patients have persistent abnormalities that reflect irreversible injury induced during the period of active inflammation. As an example, a patient in whom systemic symptoms and signs resolve and the urinalysis becomes inactive (ie, no hematuria) is considered to be in remission, even if there is persistent proteinuria and persistent or even slowly worsening renal insufficiency. In addition, late progression of the renal disease can result from factors (eg, intraglomerular hypertension) that result from initial nephron loss rather than continuing disease activity. Angiotensin inhibition may be beneficial in such patients. (See "Secondary factors and progression of chronic kidney disease" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Partial remission — Partial remission is more difficult to define. In the kidney, partial remission refers to the persistence of dysmorphic (ie, glomerular) hematuria with or without red blood cell casts despite improvement in or stabilization of the serum creatinine and disappearance of extrarenal signs of active disease (picture 1A-B). This is a smoldering process that can lead to progressive renal injury and usually indicates the need for further therapy. On the other hand, persistent proteinuria may reflect irreversible glomerular injury and, as an isolated finding, is not indicative of active disease.

Dysmorphic hematuria must be distinguished from isomorphic hematuria, which is characteristic of extraglomerular bleeding and, in patients receiving initial immunosuppressive therapy, may reflect cyclophosphamide-induced bladder toxicity. (See "Etiology and evaluation of hematuria in adults", section on 'Red cell morphology'.)

Smoldering disease in the respiratory tract is a common and difficult problem. Active vasculitis in the upper respiratory tract must be distinguished from scarring, which can progress in the absence of active disease, and infection. Similarly, a nodule in the lung may represent active vasculitis, a scar, or infection.

Cyclophosphamide resistance — True cyclophosphamide resistance is uncommon in GPA and MPA and is discussed in detail elsewhere. (See "Treatment of cyclophosphamide-resistant granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis".)

Summarized briefly, a report from the University of North Carolina defined treatment resistance as one or both of the following despite immunosuppressive therapy for at least one month [6]:

  • A progressive decline in renal function (ie, increase in serum creatinine) with persistence of an active urine sediment
  • Persistence or new appearance of any extrarenal manifestations.

In some patients, resistance is incorrectly diagnosed with persistent manifestations being due to inadequate dosing of cyclophosphamide or to inactive disease rather than ongoing inflammation.

There are at least two disease manifestations that may be relatively unresponsive to cyclophosphamide (and to other systemic therapies), but are NOT considered to represent resistant disease: orbital pseudotumor (retrobulbar masses); and subglottic stenosis, which may reflect scar rather than ongoing inflammation, and may respond best to local therapies such as triamcinolone injections and dilatation procedures (avoiding laser therapies). (See 'Management of upper airway involvement' below.)

Cannot take cyclophosphamide — Occasional patients have a contraindication to cyclophosphamide therapy or refuse such therapy because of concerns about fertility, hair loss, the risk of malignancy, or other issues. Rituximab is the drug of choice for such patients since, in two randomized trials, rituximab was as effective as cyclophosphamide in inducing remission among patients with newly diagnosed or relapsing GPA or MPA [10,11]. A potential limitation is that the duration of follow-up was limited to six to twelve months compared with the extensive long-term experience with cyclophosphamide. (See 'Rituximab' below.)

INITIAL THERAPY — Initial immunosuppressive therapy in granulomatosis with polyangiitis (Wegener’s), abbreviated as GPA, and MPA typically consists of cyclophosphamide and glucocorticoids. Rituximab may be used in patients who cannot, or refuse to take cyclophosphamide. Methotrexate may have a role in patients with mild disease, and selected patients with severe disease benefit from the addition of plasma exchange. (See 'Role of plasma exchange' below.)

The use of aggressive initial immunosuppression is justified because the mortality rate in untreated generalized GPA is as high as 90 percent at two years, usually due to respiratory or renal failure [5]. Mortality has markedly diminished with the introduction of initial therapy with cyclophosphamide and glucocorticoids.

Choice of cyclophosphamide regimen — Two cyclophosphamide dosing regimens, daily oral and monthly intravenous pulses, have been used for initial immunosuppressive therapy of GPA and MPA. Data from comparative trials have shown that the two regimens induce remission of active disease at a similar rate. Daily oral therapy has the advantage of a lower rate of relapse and the disadvantages of more leukopenia and possibly infection [12-16].

Both regimens are used clinically. This was illustrated in a community-based cohort study of 350 patients who received a new diagnosis of ANCA-associated vasculitis between 1985 and 2003 and were followed by physicians in the Glomerular Disease Collaborative Network [4]. Among the patients treated with cyclophosphamide induction, 161 received monthly intravenous therapy and 112 received daily oral therapy. Patient preference may contribute to the choice of regimen once the advantages and disadvantages are described.

Daily oral cyclophosphamide and glucocorticoids — Many clinicians favor daily oral cyclophosphamide-glucocorticoid combination therapy in the initial treatment of patients with GPA or MPA. One of the largest nonrandomized, prospective single center studies reported the outcomes in 158 patients with GPA who were treated with varying regimens at the National Institutes of Health [5]. "Standard" low-dose cyclophosphamide plus prednisone, low-dose cyclophosphamide alone, non-cyclophosphamide cytotoxic agents plus steroids, or glucocorticoids alone were administered to 133, 8, 6, and 10 patients, respectively. Cyclophosphamide was administered for a mean of two years.

The following outcomes were reported at a mean follow-up of eight years (range 6 months to 24 years):

  • Survival was 80 percent, with most deaths being due to GPA and/or side effects of therapy.
  • Significant clinical improvement was observed in more than 90 percent of patients, with 75 percent achieving complete remission.
  • Among the 98 patients followed for more than five years, almost one-half experienced remissions lasting more than five years.

Similar findings have been noted in other studies [6,17-22].

Cyclophosphamide regimen — Cyclophosphamide is given orally in a dose of 1.5 to 2 mg/kg per day. Therapy is continued until a stable remission is induced, which is usually achieved within three to six months. The white blood cell count (WBC) should be closely monitored and the cyclophosphamide dose adjusted to avoid severe leukopenia. The WBC should remain above 3000/microL and the absolute neutrophil count above 1500/microL. (See "General principles of the use of cyclophosphamide in rheumatic and renal disease", section on 'Monitoring'.)

Glucocorticoid regimen — When initiating glucocorticoid therapy, there is disagreement among experts and among the authors as to whether therapy should begin with pulse methylprednisolone (7 to 15 mg/kg to a maximum dose of 500 to 1000 mg/day for three days) in all patients or only in those with necrotizing or crescentic glomerulonephritis or more severe respiratory disease. Oral glucocorticoid therapy, either from day one or from day four if pulse methylprednisolone is given, typically consists of 1 mg/kg per day (maximum of 60 to 80 mg/day) of oral prednisone (or its equivalent).

A variety of prednisone tapering schemes have been employed. In general, the initial dose is continued for two to four weeks. If significant improvement is observed at this time, the dose of prednisone is tapered slowly, with the goal of reaching 20 mg/day by the end of two months and an overall glucocorticoid course of between six and nine months unless needed for control of persistent systemic symptoms [17,23]. Alternate day glucocorticoid regimens, once recommended in GPA, are NOT generally employed now.

Rate and time to remission — The combination of oral cyclophosphamide and glucocorticoids induces remission in 85 to 90 percent of patients, with approximately 75 percent experiencing complete remission [5,6,12,13,17-22]. Most remissions occur between two and six months [12,22]. (See 'Definition of complete remission' above.)

Reasonable estimates of the rate and time to remission with common treatment regimens were provided by CYCAZAREM (CYClophosphamide versus AZAthioprine for the maintenance of REMission), a trial of 155 patients with ANCA-associated vasculitis [22], and WGET (Wegener's Granulomatosis Etanercept Trial), a trial of 180 patients with GPA [17].

  • In CYCAZAREM, 93 percent of patients achieved remission: 77 percent within three months, and an additional 16 percent between three and six months [22].
  • In WGET, 91 percent achieved disease remission and 73 percent had a sustained complete remission lasting at least six months [17].

Relapses occurred after the induction of remission in both trials, although the rates were different: approximately 15 percent at 18 months in CYCAZAREM and approximately 50 percent at 27 months in WGET. (See "Relapsing disease in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis".)

Persistent disease-related morbidity — In the NIH study cited above, 86 percent of patients had clinically important morbidity from the disease at a mean follow-up of eight years despite adequate therapy [5]. Common extrarenal complications included hearing loss (35 percent), cosmetic and functional nasal deformities (28 percent), and tracheal stenosis (13 percent). In addition, 42 percent of patients had chronic kidney disease, with a median serum creatinine concentration of 2.6 mg/dL (229 micromol/L) at an average follow-up of seven to eight years. As expected, segmental sclerosis of previously active glomerular lesions was the most common finding on renal biopsy. Eleven percent progressed to end-stage renal disease. (See "Patient and renal outcomes in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis".)

Monthly intravenous cyclophosphamide — Monthly intravenous pulses of cyclophosphamide, which has been primarily used in systemic lupus erythematosus, has been evaluated in GPA and MPA in an attempt to lower the overall cumulative dose of cyclophosphamide. Randomized trials comparing the two approaches have shown that the rate of induction of remission with monthly intravenous cyclophosphamide compared to daily oral therapy is equivalent [12-16]. In almost all of these studies, monthly intravenous therapy had the advantages of lower total cyclophosphamide exposure and a lower rate of neutropenia and infection, but a higher rate of relapse.

The best data come from a randomized trial of 149 patients with ANCA-associated vasculitis [12]. The patients were treated prednisolone and either pulse cyclophosphamide (15 mg/kg every two to three weeks) or daily oral cyclophosphamide (2 mg/kg per day). The primary outcome was the time to remission and secondary outcomes included the relapse rate, change in renal function, adverse events, and cumulative dose of cyclophosphamide.

The following findings were noted:

  • There was no difference in the time to remission or the percentage of patients who achieved remission by nine months (88 percent in both groups). Most remissions occurred between two and six months.
  • The mean estimated glomerular filtration rate improved by a similar amount in both groups from about 30 mL/min per 1.73 m2 at study entry to 45 mL/min per 1.73 m2 at study end.
  • Among the patients who achieved remission by nine months, 19 (14.5 percent) relapsed (10 major and 9 minor). There were more relapses in the intravenous pulse cyclophosphamide group (13 versus 6), a difference that was not statistically significant but the study was not designed or powered to assess an effect on relapse.
  • Pulse cyclophosphamide compared to daily oral cyclophosphamide was associated with a significantly lower cumulative cyclophosphamide dose (8.2 versus 15.8 g) and a lower rate of leukopenia (26 versus 45 percent).

These results are consistent with a prior meta-analysis that included 143 patients from three small randomized trials [16]. Intravenous cyclophosphamide was at least as effective as oral cyclophosphamide for inducing remission and was associated with a significantly lower rate of leukopenia and infection and a trend toward a higher rate of relapse.

Alternative regimens — Because of the toxicity associated with the prolonged administration of oral cyclophosphamide, several alternative regimens have been evaluated for initial therapy. None has supplanted the oral cyclophosphamide-glucocorticoid regimen, although rituximab is the preferred therapy for patients who cannot take or refuse cyclophosphamide.

Rituximab — Two randomized trials have suggested that rituximab may be an effective alternative to cyclophosphamide for the initial treatment of patients who have newly diagnosed disease or have relapsed following treatment with cyclophosphamide or other immunosuppressive therapy [10,11].

  • A multicenter noninferiority trial (the RAVE trial) compared induction therapy with rituximab (375 mg/m2 per week for four weeks) or with oral cyclophosphamide (2 mg/kg per day) in 197 patients with GPA (75 percent of enrolled patients) or MPA (24 percent); 49 percent of patients were newly diagnosed and the remainder had relapsing disease [11]. All patients received one to three pulses of methylprednisolone (1000 mg) followed by prednisone (1 mg/kg per day). Rituximab was noninferior to cyclophosphamide in inducing remission by six months (64 versus 53 percent). However, in the 100 patients with relapsing disease, rituximab was superior to cyclophosphamide in inducing remission (67 versus 42 percent). There was no difference in the number of adverse events.
  • In the second trial (RITUXVAS), 44 patients with newly diagnosed ANCA-associated renal vasculitis were assigned in a 3:1 ratio to receive methylprednisolone (1000 mg) followed by oral methylprednisolone (1 mg/kg per day with reduction to 5 mg per day by the end of six months) plus either rituximab (375 mg/m2 per week for four weeks) with two intravenous cyclophosphamide pulses (15 mg/kg), or intravenous cyclophosphamide for three to six months followed by azathioprine [10]. Patients who received rituximab who had progressive disease within the first six months were given a third dose of cyclophosphamide (15 mg/kg per day). At 12 months, there was no difference in the rate of sustained remission (defined as the absence of disease activity for at least six months) between the rituximab and cyclophosphamide only groups (76 versus 82 percent). There was also no difference between groups in the rate of adverse events.

These studies suggest that rituximab is as effective as cyclophosphamide for the initial treatment of GPA and MPA or for patients with relapsing disease. However, both studies are limited in the duration of follow-up [24]. Longer-term results from the RAVE trial are expected in 2011. Until such data are available, we prefer cyclophosphamide to rituximab as initial therapy for GPA and MPA. However, rituximab is the preferred therapy for patients who cannot take or refuse cyclophosphamide.

Methotrexate — Low-dose weekly oral methotrexate has been used as initial therapy in patients with GPA who have non-organ threatening and non-life threatening disease [23,25-29] and, as discussed elsewhere, as maintenance therapy in patients treated initially with cyclophosphamide or methotrexate. (See "Maintenance immunosuppressive therapy in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis", section on 'Methotrexate'.)

The best data on the efficacy of methotrexate come from the randomized NORAM trial that compared methotrexate and cyclophosphamide for both induction and remission of ANCA-associated vasculitis without significant renal involvement (mean serum creatinine 1.0 mg/dL (85 micromol/L) and microscopic hematuria in only 28 percent) [27]. The trial enrolled 89 patients with newly diagnosed GPA and 6 with MPA, all of whom had "early generalized disease." The exclusion criteria were signs of potentially severe systemic disease as manifested by a serum creatinine greater than 1.7 mg/dL (150 micromol/L), red blood cell casts, severe hemoptysis, cerebral infarction due to vasculitis, orbital pseudotumor, or rapidly progressive neuropathy.

The patients were assigned to methotrexate (20 to 25 mg per week orally) or cyclophosphamide (2 mg/kg per day orally); all received prednisolone. Therapy was gradually tapered and withdrawn by 12 months.

The following findings were noted:

  • At six months, 90 and 94 percent of patients in the methotrexate and cyclophosphamide arms, respectively, achieved remission, although time to remission was two months longer in the methotrexate group.
  • Among the patients who achieved remission, the relapse rate at 18 months was significantly higher with methotrexate (70 versus 47 percent with cyclophosphamide).
  • In terms of adverse outcomes, there was a higher incidence of leukopenia among those treated with cyclophosphamide and a higher incidence of liver function test abnormalities among those treated with methotrexate. Two patients in each group died.

Thus, methotrexate was as effective as cyclophosphamide for the induction of remission in patients with mild disease, but was associated with a significantly higher relapse rate. The 2008 European League Against Rheumatism (EULAR) guidelines recommended the combination of oral or parenteral methotrexate and glucocorticoids as a less toxic alternative than cyclophosphamide for induction of remission in non-organ threatening and non-life threatening ANCA associated vasculitis [29]. Rheumatologists have the most experience with methotrexate for induction therapy, while most nephrologists have little or no experience with this approach.

Given the higher relapse rate, methotrexate should probably be used primarily for limited disease not involving the kidney. It may also be used in selected patients who do not tolerate cyclophosphamide or rituximab. Given the risk of toxicity in patients with renal dysfunction, methotrexate should not be used when the estimated glomerular filtration rate is below 50 mL/min. (See "Major side effects of low-dose methotrexate".)

Glucocorticoids alone — Glucocorticoid monotherapy is NOT generally considered for remission induction, since the reported remission rate is much lower than in combination with cyclophosphamide (56 versus 85 percent), and the rate of relapse much higher [6]. This is particularly true for patients with severe disease manifestations, such as glomerulonephritis. Among 57 patients evaluated at the National Institutes of Health who were initially treated with prednisone alone, none of those with renal disease (45 patients) experienced sustained improvement, and 55 of the 57 (96 percent) eventually required cytotoxic therapy [30].

Role of plasma exchange — Several controlled trials of patients with GPA, MPA, or the related disorder segmental necrotizing glomerulonephritis with no immune deposits on pathologic examination (which is thought to represent renal-limited vasculitis) have demonstrated no overall benefit for the renal disease from plasma exchange, with the possible exception of patients who one or more of the following [19,31-37]:

  • Severe renal disease, which has been variably defined
  • Concurrent anti-glomerular basement membrane (GBM) antibody disease
  • Severe pulmonary hemorrhage

Severe active renal disease — Two trials have evaluated the efficacy of plasma exchange in patients with GPA or MPA who have severe active renal disease. Potential efficacy of plasma exchange was evaluated in an initial randomized trial in which 48 patients with focal necrotizing glomerulonephritis were assigned to immunosuppressive therapy with or without plasma exchange; pulse methylprednisolone was not given [31]. There was no difference in outcome among the 17 patients with a serum creatinine concentration of less than 5.7 mg/dL (500 micromol/L) or the 12 with higher serum creatinine concentrations in whom dialysis was not required. In contrast, plasma exchange appeared to be of benefit in the patients who required dialysis.

The role of plasma exchange in patients with severe renal disease was also addressed in the randomized Methylprednisolone versus Plasma Exchange (MEPEX) trial [37]. This trial enrolled 137 patients with a new diagnosis of GPA or MPA, pauci-immune glomerulonephritis, and a serum creatinine concentration above 5.7 mg/dL (500 micromol/L). The mean serum creatinine at presentation was 8.3 mg/dL (735 micromol/L) and 69 percent required dialysis which, in the preceding trial, identified patients who benefited from plasma exchange.

The patients were assigned randomly to receive either seven sessions of plasma exchange over the first two weeks after diagnosis or methylprednisolone 1 g/day for three days. In addition to these therapies, patients received prednisolone (1 mg/kg per day, tapered over six months) and cyclophosphamide (2.5 mg/kg per day for three months), followed by azathioprine for remission maintenance.

The major results of the MEPEX trial are as follows:

  • Plasma exchange was associated with a significantly higher likelihood of being alive and having independent renal function at three months (69 versus 49 percent in the methylprednisolone group).
  • Plasma exchange was associated with a significant reduction in the risk of progression to end-stage renal disease at one year (19 versus 43 percent).
  • The mortality rate was high in both groups (27 and 24 percent at one year). The majority of deaths occurred in the first three months of treatment. Of the 35 deaths in the trial, 19 were related to infection, 6 to pulmonary hemorrhage, and 4 to cardiovascular events.

The MEPEX trial had a number of important shortcomings:

Despite these limitations, the results of the MEPEX trial support the notion that the addition of plasma exchange to cyclophosphamide and glucocorticoid therapy may enhance the recovery of renal function among patients who present with severe renal dysfunction (serum creatinine above 5.7 mg/dL (500 micromol/L)) during the acute phase of disease.

In a meta-analysis of nine trials (of which the MEPEX was by far the largest) and including 387 patients, the addition of plasma exchange to standard care decreased the pooled risk of end-stage renal disease or death (RR 0.8, 95% CI, 0.65-0.99) and of end-stage renal disease alone (RR 0.64, 95% CI 0.47-0.88) [38]. The serum creatinine of participants ranged from 3.2 to 13.5 mg/dL (283 to 1193 mmol/L).

However, although these results were statistically significant, the calculated optimal information size (sample size) required to be confident of a risk reduction of roughly 25 percent is 1478 patients. Thus, reliable conclusions cannot be drawn from this underpowered analysis, although it supports the role of plasma exchange as a promising adjunctive therapy.

For patients with advanced renal dysfunction without concurrent anti-GBM antibody disease, we suggest seven sessions of plasma exchange over two weeks (60 mL/kg at each session). Albumin is the preferred replacement fluid in patients without bleeding or a recent renal biopsy. For patients with bleeding or a recent biopsy, we suggest that one to two liters of fresh frozen plasma should be substituted for albumin at the end of the procedure to reverse pheresis-induced depletion of coagulation factors.

Among patients who develop severe infection in the setting of plasma exchange, a single infusion of intravenous immune globulin (100 to 400 mg/kg) can be given to partially replenish antibody levels.

Concurrent anti-GBM antibodies — Based entirely upon presumed benefits in patients with anti-GBM antibody disease alone, plasma exchange is usually used in combination with immunosuppressive therapy in patients with ANCA-associated vasculitis who also have anti-GBM antibodies [39,40]. (See "Treatment of anti-GBM antibody (Goodpasture's) disease", section on 'Plasmapheresis' and "Clinical spectrum of antineutrophil cytoplasmic antibodies", section on 'Anti-GBM antibody disease'.)

Pulmonary hemorrhage — Although randomized controlled trials have not been performed, patients with pulmonary hemorrhage should be treated with plasma exchange [40,41]. This strategy is based upon the theoretical benefit of removing ANCA by plasma exchange and the observed efficacy of plasma exchange in patients with pulmonary hemorrhage due to anti-GBM antibody disease.

Benefits from plasma exchange in this setting were suggested in a retrospective review of 20 patients who presented between 1995 and 2001 with diffuse alveolar hemorrhage (DAH) and ANCA-associated small vessel vasculitis [41]. Fourteen of the patients presented with impaired renal function, with the average serum creatinine concentration being 4.7 mg/dL (415 micromol/L).

All patients underwent daily full plasma volume plasma exchange until DAH improved, which was then changed to alternative day apheresis therapy until the DAH resolved. The replacement fluid was 5 percent albumin and two units of fresh frozen plasma at the end of apheresis. All patients also received intravenous methylprednisolone (7 mg/kg per day) for three days, and all but two received intravenous cyclophosphamide (0.5 g/m2 of body surface area). Additional therapy included ventilatory support and hemodialysis for nine and seven patients, respectively.

DAH resolved in all 20 patients, with the mean number of apheresis treatments being 6.15 (range of 4 to 9). There were no complications due to apheresis. One patient died because of a pulmonary embolism. Among the seven patients who did not require dialysis, the serum creatinine fell significantly by the time of discharge (4.5 to 2.4 mg/dL (398 to 212 micromol/L)).

The results of this study must be interpreted in light of its retrospective design and lack of a control group. In addition, because all patients in the review received conventional therapies (generally cyclophosphamide and glucocorticoids) in addition to plasma exchange, independent effects of plasma exchange are impossible to delineate.

For patients with pulmonary hemorrhage, we suggest seven sessions of plasma exchange over two weeks (60 mL/kg at each session). Fresh frozen plasma is the preferred replacement fluid, with one to two liters being given at the end of the procedure to reverse pheresis-induced depletion of coagulation factors.

Among patients who develop severe infection in the setting of plasma exchange, a single infusion of intravenous immune globulin (100 to 400 mg/kg) can be given to partially replenish antibody levels.

Treatment-associated toxicity — The cyclophosphamide plus glucocorticoid regimen is associated with important toxicity and does not reverse tissue necrosis. In addition to the toxicities discussed below, cytotoxic agents are toxic to the fetus. (See "Pregnancy in women with underlying renal disease" and "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation" and "General principles of the use of cyclophosphamide in rheumatic and renal disease".)

In the 1992 NIH study cited above, cyclophosphamide therapy resulted in a 57 percent incidence of either amenorrhea lasting more than one year or inability to become pregnant; gonadal function in men was not evaluated. Other reported toxicities included cystitis (50 percent), bladder cancer (5.6 percent), myelodysplasia (2 percent), and lymphoma (0.7 percent) [5]. A detailed discussion of the measures available to minimize toxicity associated with this regimen can be found in a separate topic review. (See "General toxicity of cyclophosphamide and chlorambucil in inflammatory diseases".)

Reported toxicities of extended glucocorticoid therapy in the NIH study were cataracts (21 percent), diabetes mellitus (8 percent), osteopenia, fractures (11 percent), and aseptic necrosis of bone (3 percent). In addition, severe gastritis may develop and result in gastrointestinal bleeding in patients at increased risk. (See "Major side effects of systemic glucocorticoids".)

PCP prophylaxis — Pneumocystis carinii (jiroveci) pneumonia (PCP) and other opportunistic infections are potentially fatal complications of immunosuppressive therapy in GPA or MPA. In one series, for example, PCP developed in 11 of 180 (6 percent) patients with GPA, all of whom were treated with daily glucocorticoids and a second immunosuppressive drug [42]. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in non-HIV-infected patients".)

Prophylaxis may be both cost-saving and life-prolonging in this setting. We administer prophylaxis during induction therapy; the suggested regimen varies with the regimen used for initial immunosuppression:

Among patients who have been treated with trimethoprim-sulfamethoxazole for prophylaxis during induction, we continue trimethoprim-sulfamethoxazole when azathioprine is used for maintenance therapy and switch to atovaquone when methotrexate is used for maintenance therapy.

Some patients have low CD4-positive T cell counts for prolonged periods after the cessation of cyclophosphamide and require prolonged PCP prophylaxis, with glucocorticoids being tapered to the lowest possible dose. If patients treated with trimethoprim-sulfamethoxazole develop neutropenia, which is a possible side effect, we switch to atovaquone.

MANAGEMENT OF UPPER AIRWAY INVOLVEMENT — The consequences of upper airway involvement are often not improved by initial immunosuppressive therapy and are NOT considered resistant disease.

Nasal ulcers and crusting are common manifestations of upper airway disease in ANCA-associated vasculitis, particularly in GPA. It is often difficult to determine if these lesions are attributable to vasculitis, infection, or both. Although oral antibiotics are frequently required to treat more severe infections in the upper respiratory tract, some experts prefer a trial of topical therapy for nasal ulcers and crusting. This approach may involve either direct application of antibiotic ointment just inside of the nares and/or nasal irrigation with a saline solution to which topical antibiotics have been added. Nasal saline sprays are available over the counter or may be made up as one quart of water with one teaspoon of brine or pickling salt and one teaspoon of baking soda.

Lesions of the tracheobronchial tree can cause a variety of problems. The most serious complications include tracheal or bronchial stenosis that can lead to respiratory failure or postobstructive pneumonia. Treatment options for these problems include airway dilation with or without stenting. For subglottic stenosis, intralesional injection of glucocorticoids in combination with endoscopic dilation may avoid the need for more invasive surgical procedures [44,45].

Tracheostomy should be avoided whenever possible. When tracheostomy is necessary, most patients are able to have the tracheostomy tube removed. This was illustrated in a retrospective report of 27 patients with ANCA-associated vasculitis: 11 required tracheostomy and 3 could not be decannulated [46]. (See "Diagnosis and management of central airway obstruction".)

Stenosing lesions of the nasal passages and destructive lesions of the nasal cartilage and bones may cause discomfort and/or be disfiguring. Reconstructive surgery may provide a functional airway and can restore a more nearly normal appearing nose [47]. Grafts prepared from a patient's costal or auricular cartilage, iliac or other bone, or dura have been used with varying success.

MANAGEMENT IN PREGNANCY — There is only limited information on pregnancy complicated by GPA or MPA, although both newly diagnosed and relapsing GPA can occur during pregnancy or in the postpartum period [48,49]. As with active disease in nonpregnant patients, prednisone alone is relatively ineffective, particularly for moderate to severe disease, while remission can be induced by combined therapy with cyclophosphamide.

The major challenges in treating active disease during pregnancy are that potentially serious adverse effects can occur with both cyclophosphamide and with alternative therapies such as mycophenolate. In addition, there are insufficient data to assess the safety of rituximab, (which has been used for non-pregnant patients who cannot tolerate cyclophosphamide) in pregnancy. (See "Treatment of cyclophosphamide-resistant granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis", section on 'Mycophenolate mofetil' and "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Rituximab'.)

Fetal cyclophosphamide exposure during the first trimester has been associated with a high risk of skeletal and palatal defects, as well as malformations of the limbs and eyes. The fetal risk is much smaller with cyclophosphamide therapy during the second and third trimesters, but pancytopenia and impaired fetal growth can occur. (See "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Cyclophosphamide' and "General toxicity of cyclophosphamide and chlorambucil in inflammatory diseases", section on 'Teratogenicity'.)

Mycophenolate mofetil (MMF) increases the risk of miscarriage and congenital malformation such as cleft lip and palate. As a result, MMF has a boxed warning for these complications and some consider MMF to be contraindicated in pregnancy. (See "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Mycophenolate mofetil'.)

As a result, there are three major therapeutic approaches in women with significant active disease during pregnancy: the use of safer immunosuppressive drugs; therapeutic abortion prior to initiation of cyclophosphamide-based therapy, and the use of rituximab, which has insufficient safety data for use in pregnancy.

The safer immunosuppressive drugs that have been effective in GPA and MPA include glucocorticoids, azathioprine, and cyclosporine (or tacrolimus), particularly in mild to moderate disease. These drugs can also be tried for severe disease. Alternatives that could be considered include cyclophosphamide or rituximab in the second or third trimester once organogenesis is complete.

MAINTENANCE THERAPY — Once remission is induced with cyclophosphamide therapy (which usually occurs within three to six months), patients are switched to maintenance therapy with less toxic immunosuppressive drugs, usually azathioprine or methotrexate. This issue is discussed in detail separately. (See "Maintenance immunosuppressive therapy in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis".)

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SUMMARY AND RECOMMENDATIONS — Granulomatosis with polyangiitis (Wegener’s), which can be abbreviated as GPA, and microscopic polyangiitis (MPA) are related systemic vasculitides that are associated with antineutrophil cytoplasmic antibodies (ANCA). GPA and MPA have similar features on renal histology and similar outcomes. Therapy of GPA and MPA has two components: the induction of remission; and maintenance immunosuppressive therapy to prevent relapse. Induction of complete remission, defined as the absence of active disease, is the goal of initial immunosuppressive therapy. (See 'Definition of complete remission' above.)

Cyclophosphamide or rituximab — Initial therapy with cyclophosphamide and glucocorticoids, which is preferred in the great majority of patients, induces remission in 85 to 90 percent of patients, usually with two to six months. Two randomized trials have suggested that rituximab may be an effective alternative to cyclophosphamide for the initial treatment of patients who have newly diagnosed disease but both studies are limited in the duration of follow-up. (See 'Rate and time to remission' above and 'Rituximab' above.)

  • For all patients with newly diagnosed organ-threatening or life-threatening disease, we recommend initial immunosuppressive therapy with glucocorticoids plus either cyclophosphamide (either oral or intravenous) or rituximab rather than other therapies or glucocorticoids alone (Grade 1A).
  • Until long-term data on the effectiveness and safety of rituximab are available, for patients with newly diagnosed organ-threatening or life-threatening disease who do not have a contraindication to, and do not refuse to take cyclophosphamide, we suggest initial immunosuppressive therapy with the combination of cyclophosphamide (either oral or intravenous) and glucocorticoids rather than rituximab and glucocorticoids (Grade 2B).

    There are two cyclophosphamide regimens: daily oral and monthly intravenous. Data from comparative trials have shown that the two regimens induce remission of active disease at a similar rate. Daily oral therapy has the advantage of a lower rate of relapse and the disadvantages or more leukopenia and possibly infection. Patient preference may contribute to the choice of regimen once the advantages and disadvantages are described. Regardless of the regimen chosen, close follow-up and monitoring for the development of neutropenia are indicated. (See 'Choice of cyclophosphamide regimen' above.)

  • For all patients with organ-threatening or life-threatening disease who cannot or refuse to take cyclophosphamide, we recommend initial immunosuppressive therapy with rituximab and glucocorticoids rather than other therapies (Grade 1B). (See 'Cannot take cyclophosphamide' above.) The preferred regimen is that used in the RAVE trial:

Glucocorticoid therapy

  • We recommend glucocorticoid therapy in all patients with active GPA or MPA (Grade 1B). The decision to initiate glucocorticoids with intravenous pulse methylprednisolone depends upon the severity of the disease. (See 'Glucocorticoid regimen' above.)

  • For patients with necrotizing or crescentic glomerulonephritis or severe respiratory disease, we suggest pulse methylprednisolone followed by oral prednisone or its equivalent (Grade 2C). The preferred regimen is 7 to 15 mg/kg to a maximum dose of 500 to 1000 mg/day for three days followed by oral prednisone on day four at a dose of 1 mg/kg per day (maximum of 60 to 80 mg/day).
  • For patients who do not have necrotizing glomerulonephritis or severe respiratory disease, we suggest oral prednisone or its equivalent rather than initial pulse intravenous therapy (Grade 2C). A suggested dose is 1 mg/kg per day (maximum of 60 to 80 mg/day) beginning on day one. However, some clinicians prefer pulse methylprednisolone for three days in such patients.
  • Oral prednisolone or its equivalent is continued at the initial dose for two to four weeks. If significant improvement is observed at this time, the dose of prednisone is tapered slowly, with the goal of reaching 20 mg/day by the end of two months and an overall glucocorticoid course of between six and nine months. We suggest NOT using alternate day glucocorticoid regimens (Grade 2C).

Methotrexate therapy

  • Methotrexate given with glucocorticoid therapy is an alternative to cyclophosphamide for highly selected patients with non-organ-threatening and non-life-threatening disease such as those with pulmonary nodules or infiltrates without respiratory compromise, and/or ocular disease. Methotrexate should NOT be given to patients with an estimated glomerular filtration rate less than 50 mL/min. (See 'Methotrexate' above.)

  • A suggested regimen is oral methotrexate at an initial dose of 0.3 mg/kg (but not exceeding 15 mg) once per week, with increases of 2.5 mg each week to a maximum dose of 25 mg once per week. Since methotrexate is a structural analogue of folic acid that can competitively inhibit the binding of dihydrofolic acid (FH2) to the enzyme dihydrofolate reductase (DHFR), folic acid (1 to 2 mg/day) or folinic acid (2.5 to 5 mg per week, 24 hours after methotrexate) should be given concurrently to reduce potential toxicity.

Plasma exchange

  • The addition of plasma exchange to cyclophosphamide and glucocorticoid therapy may enhance the recovery of renal function among patients who present with severe renal dysfunction during the acute phase of disease. We suggest plasma exchange for patients with GPA or MPA who have anti-GBM antibodies as well as ANCA; for patients with severe pulmonary hemorrhage on presentation or those with worsening pulmonary hemorrhage despite the combination of high-dose glucocorticoids and cyclophosphamide; and for patients who have advanced renal dysfunction at presentation, as defined by a serum creatinine level above 5.7 mg/dL (500 micromol/L) and/or dialysis dependence (Grade 2C). (See 'Role of plasma exchange' above.)

  • For patients with advanced renal dysfunction, we suggest seven sessions of plasma exchange over two weeks (60 mL/kg at each session). A more prolonged regimen is used in patients with anti-GBM disease. (See "Treatment of anti-GBM antibody (Goodpasture's) disease".)
  • Among patients who have had a recent renal biopsy or have pulmonary hemorrhage, we suggest that one to two liters of fresh frozen plasma should be substituted for albumin at the end of the procedure to reverse pheresis-induced depletion of coagulation factors. For patient who have no evidence of hemorrhage or who are not at risk for bleeding, we suggest that albumin be used as the replacement fluid.
  • Among patients who develop severe infection in the setting of plasma exchange, a single infusion of intravenous immune globulin (100 to 400 mg/kg) can be given to partially replenish antibody levels.

Role of PCP prophylaxis — Pneumocystis carinii (jiroveci) pneumonia (PCP) and other opportunistic infections are potentially fatal complications of immunosuppressive therapy in GPA. The estimated incidence of PCP is approximately 6 percent. The suggested approach to prophylaxis against PCP infection during initial immunosuppressive therapy is discussed above. (See 'PCP prophylaxis' above.)

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