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Initial immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis
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Initial immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis
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Literature review current through: Sep 2017. | This topic last updated: Jan 04, 2017.

NEW TERMINOLOGY — In January 2011, the Boards of Directors of the American College of Rheumatology (ACR), the American Society of Nephrology (ASN), and the European League Against Rheumatism (EULAR) recommended that the name "Wegener's granulomatosis" be changed to "granulomatosis with polyangiitis," abbreviated as GPA [1-3]. This change reflects a plan to gradually shift from honorific eponyms to a disease-descriptive or etiology-based nomenclature.

INTRODUCTION — Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are related systemic vasculitides that, along with eosinophilic granulomatosis with polyangiitis (Churg-Strauss), make up the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides. Both GPA and MPA are associated with ANCA, have many identical clinical manifestations, have many similar histologic features, and have similar outcomes. There are, however, several differences between these disorders. (See "Clinical manifestations and diagnosis of granulomatosis with polyangiitis and microscopic polyangiitis", section on 'Clinical presentation'.)

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

The initial immunosuppressive therapy of GPA and MPA will be reviewed here (algorithm 1). 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 and microscopic polyangiitis" and "Treatment-resistant granulomatosis with polyangiitis and microscopic polyangiitis" and "Identification and management of relapsing disease in granulomatosis with polyangiitis and microscopic polyangiitis" and "Clinical manifestations and diagnosis of granulomatosis with polyangiitis and microscopic polyangiitis" and "Prognosis in granulomatosis with polyangiitis and microscopic polyangiitis, and management of those who develop end-stage renal disease".)

GENERAL PRINCIPLES

Assessment of disease activity — A variety of methods have been used to assess disease activity in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). As an example, the Birmingham Vasculitis Activity Score (BVAS) has been applied to patients with either GPA or MPA. The BVAS system incorporates data on disease manifestations in nine categories (ie, general symptoms such as arthralgia, arthritis, and fever, plus involvement of eight major organ systems) and has been the main outcome measurement tool used in clinical trials of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis [4]. Evaluation of patients using the BVAS system is mostly performed in research studies and less commonly in clinical practice. (See "Overview of the management of vasculitis in adults", section on 'Monitoring' and "Overview of the management of vasculitis in adults".)

Who should be treated? — Immunosuppressive therapy is warranted in almost all patients with active GPA or MPA. The choice of therapy is discussed below. (See 'Overall approach to initial therapy' below.)

Even patients with advanced renal disease, as assessed by serum creatinine concentration or the need for dialysis at presentation, may receive benefit from aggressive treatment. As examples:

In a study of 155 patients with GPA or MPA and crescentic glomerulonephritis, 87 percent required hemodialysis at the time of kidney biopsy [5]; all patients were treated with immunosuppressive medications, usually with cyclophosphamide and glucocorticoids. At four months, 14 percent died, and 35 percent were alive but required dialysis; 51 percent did not require dialysis and had no evidence of active vasculitis. The likelihood of having improved renal function was lower if the biopsy showed a high degree of chronic damage, although some such patients did improve.

In another report, remission was induced in 72 percent of 240 patients with an estimated glomerular filtration rate (eGFR) of ≤30 mL/min per 1.73 m2, 68 percent of 188 patients with an eGFR of ≤20 mL/min per 1.73 m2, and 57 percent of 96 patients with an eGFR of ≤10 mL/min per 1.73 m2 [6].

Similarly, patients with longstanding upper or lower airway disease may benefit from initiation of immunosuppressive therapy.

Definition of complete remission — Induction of complete remission is the goal and expectation of treatment with immunosuppressive therapy in GPA or MPA and is defined as the absence of active disease (ie, the absence of any clinical manifestations that are deemed secondary to ongoing active vasculitis) [4,7-10].

Renal remission — If there is no active renal inflammation, then hematuria and, if present, red cell casts should remit. Remission is defined in such patients as less than 5 red cells per high-power field in a centrifuged urine sediment. Persistent hematuria should raise concern for ongoing glomerulonephritis. However, there are 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) [11]. (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 isomorphic hematuria raises the possibility of cyclophosphamide-induced bladder cancer, which is not typically seen with the usually short duration of therapy with cyclophosphamide now used in patients with GPA or MPA [11]. (See "Epidemiology and risk factors 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.

Persistent hematuria may be due to the coexistence of thin basement membrane disease. This usually benign condition is identified by kidney biopsy, and therefore, its presence should be known in patients who are treated for glomerulonephritis due to GPA or MPA. (See "Thin basement membrane nephropathy (benign familial hematuria)".)

Nonglomerular causes of hematuria, such as nephrolithiasis, urethral injury from catheterization, or infection (urethritis or cystitis), may also occur in patients with GPA or MPA.

Distinguishing active disease, irreversible injury, and treatment-related damage — It is important but sometimes difficult to differentiate evidence of active vasculitis from permanent damage, which can be due either to the underlying disease or to its treatment [12]. Complete remission does not mean that all parameters have to return to baseline [7]. Many patients have persistent abnormalities that reflect irreversible injury induced during the period of active inflammation:

Chronic upper airway mucosal damage with nasal crusting or a residual lung nodule (scar)

Chronic but stable peripheral neuropathic sensory changes

Persistent proteinuria and renal insufficiency

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, a malignancy in a patient treated with an alkylating agent, or an infection. (See 'Distinguishing active disease, irreversible injury, and treatment-related damage' above.)

INITIAL THERAPY — Initial immunosuppressive therapy in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) typically consists of glucocorticoids combined with either cyclophosphamide or rituximab (algorithm 1) [13-15]. Some studies have described the use of both cyclophosphamide and rituximab for initial therapy (rather than using one of these two agents), although this approach is controversial. Selected patients with severe disease may 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 [7]. Mortality has markedly diminished with the introduction of initial therapy with cyclophosphamide and glucocorticoids [16].

Methotrexate in combination with glucocorticoids may have a role as initial therapy in patients with non-organ-threatening and non-life-threatening disease (eg, patients with rhinosinusitis, arthritis, and/or pulmonary nodules with no other major organ involvement).

Overall approach to initial therapy — Our approach to initial therapy depends upon the severity of the disease and the organ systems involved. From an initial therapeutic perspective, there are several options (algorithm 1):

Non-organ-threatening and non-life-threatening disease – This group of patients has no evidence for "active" glomerulonephritis (ie, normal serum creatinine and no red cell casts or proteinuria) and no organ-threatening or life-threatening manifestations (eg, absence of pulmonary hemorrhage, cerebral vasculitis, progressive neuropathy, orbital pseudotumor, gastrointestinal bleeding, pericarditis, or myocarditis). Such patients may have rhinosinusitis, arthritis, and/or pulmonary nodules. Non-organ-threatening and non-life-threatening disease can still result in substantial disease burden and long-term damage.

Organ-threatening or life-threatening disease – Other patients with GPA or MPA are classified into this group for the purpose of initial therapy. Such patients may have manifestations including (but not limited to) marked pulmonary hemorrhage, rapidly deteriorating renal function, or motor neuropathy.

Based upon these groups of disease severity, our therapeutic approach is as follows (algorithm 1):

Non-organ-threatening and non-life-threatening disease – In these patients, we suggest a regimen of glucocorticoids in combination with methotrexate. Initial treatment of nonsevere disease with rituximab is also reasonable, especially if there is a contraindication to methotrexate use. Those who are treated with methotrexate and who do not respond or who have progressive disease should be treated with either cyclophosphamide or rituximab.

Organ-threatening or life-threatening disease – The authors and editors of this topic do not agree on the preferred initial immunosuppressive regimen in such patients. Overall, we recommend a regimen consisting of glucocorticoids in combination with either cyclophosphamide (oral or intravenous) or rituximab. Some authors/editors favor a cyclophosphamide-based regimen as initial therapy, while others choose a rituximab-based regimen for the majority of patients.

In certain patients, such as those with concerns about fertility or alopecia and those who have been previously treated with a course of cyclophosphamide, rituximab is the preferred initial therapy. (See 'Contraindications to or refusal of cyclophosphamide' below.)

Some authorities treat with glucocorticoids in combination with both cyclophosphamide and rituximab. However, no trials have shown that this approach is superior to the use of either cyclophosphamide or rituximab as initial therapy. (See 'Combination cyclophosphamide and rituximab' below.)

Also, we suggest plasma exchange in addition to glucocorticoids and either cyclophosphamide or rituximab in patients with GPA or MPA who have one or more of the following features (algorithm 1) (see 'Role of plasma exchange' below):

Patients who have rapidly deteriorating kidney function or severe kidney dysfunction (eg, those who have a serum creatinine above 4.0 mg/dL [350 micromol/L] or who require dialysis).

Patients who have pulmonary hemorrhage – Some contributors to this topic would treat all patients who have pulmonary hemorrhage with plasma exchange, while others would use plasma exchange in only those patients who also have severe respiratory impairment (eg, dyspnea or hypoxia) or if the patient does not respond quickly to therapy with intravenous glucocorticoids.

Patients who have a concomitantly positive anti-glomerular basement membrane (anti-GBM) autoantibody.

Details of cyclophosphamide-based regimens, cyclophosphamide resistance, and contraindications to cyclophosphamide are discussed below; the adverse effects associated with cyclophosphamide therapy are presented elsewhere. (See 'Cyclophosphamide-based regimen' below and "General toxicity of cyclophosphamide in rheumatic diseases".)

Details of rituximab-based regimens are discussed below; the adverse effects associated with rituximab therapy are presented elsewhere. (See 'Rituximab-based regimen' below and "Rituximab and other B cell targeted therapies for rheumatoid arthritis" and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab'.)

Glucocorticoids are given in combination with cyclophosphamide or rituximab. Prolonged glucocorticoid monotherapy should not be used [8,17]. Dosing of glucocorticoids is discussed below. (See 'Glucocorticoid dosing' below.)

The use of methotrexate in non-organ-threatening and non-life-threatening disease is discussed below. (See 'Methotrexate in non-organ- and non-life-threatening disease' below.)

In addition, we administer prophylaxis against opportunistic infections during induction therapy; the suggested regimen varies with the regimen used for initial immunosuppression. (See 'Prophylaxis against infection' below.)

Trials comparing cyclophosphamide with rituximab — Two randomized trials have suggested that rituximab is 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 [18,19], although, in one of these two trials, those assigned to rituximab also received cyclophosphamide. The rates of serious adverse events were similar with both drugs:

The RAVE trial was a randomized, placebo-controlled, multicenter noninferiority trial that 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 (25 percent); 49 percent of patients were newly diagnosed, and the remainder had relapsing disease [18]. 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) at six months. There was no difference in the number of adverse events.

Of the 197 patients initially enrolled in RAVE, the 146 patients who achieved complete remission were followed through month 18 [20]. In this trial, rituximab-treated patients received no further therapy, while cyclophosphamide-treated patients were converted to azathioprine immunosuppression within the first six months of treatment. At 18 months, the proportion of patients remaining in complete remission was similar comparing rituximab- with cyclophosphamide-based induction (39 versus 33 percent). In addition, there were no differences between the treatment groups in the number of deaths or the rate of severe infections.

In the second trial (RITUXVAS), 44 patients with newly diagnosed antineutrophil cytoplasmic autoantibody (ANCA)-associated renal vasculitis were assigned in a 3:1 ratio to receive intravenous 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) in combination with two intravenous cyclophosphamide pulses (15 mg/kg) or intravenous cyclophosphamide (15 mg/kg every two weeks for three doses followed by infusions every three weeks) for three to six months followed by azathioprine [19,21]. Patients who received rituximab who had progressive disease within the first six months were given a third dose of cyclophosphamide (15 mg/kg).

At 12 and 24 months in RITUXVAS, 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 at 12 months.

Cyclophosphamide-based 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. The CYCLOPS trial, discussed below, found an increased risk of adverse events (especially leukopenia) with oral dosing but a lower relapse rate than with intravenous dosing [22-27]. This higher relapse rate is probably less relevant with the maintenance therapy regimens that are now used.

Daily oral cyclophosphamide — Some 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 (NIH) [7]. "Standard" low-dose cyclophosphamide plus prednisone, low-dose cyclophosphamide alone, non-cyclophosphamide cytotoxic agents plus glucocorticoids, 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 of six 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 [8,28-33].

Oral cyclophosphamide dosing — 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 should be closely monitored (eg, weekly), and the cyclophosphamide dose should be adjusted to avoid severe leukopenia. The white blood cell count should remain above 3500/microL, and the absolute neutrophil count should remain above 1500/microL. The dose of oral cyclophosphamide should also be reduced in patients with severe renal dysfunction (table 1). (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Monitoring of oral CYC dosing'.)

Patients receiving oral cyclophosphamide should also receive glucocorticoids. The regimen is discussed below. (See 'Glucocorticoid dosing' below.)

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 [7,8,22,23,28-33]. Most remissions occur between two and six months [22,33]. (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 [33], and WGET (Wegener's Granulomatosis Etanercept Trial), a trial of 180 patients with GPA [28]:

In CYCAZAREM, 93 percent of patients achieved remission: 77 percent within three months and an additional 16 percent between three and six months [33]

In WGET, 91 percent achieved disease remission, and 73 percent had a sustained complete remission lasting at least six months [28]

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 "Identification and management of relapsing disease in granulomatosis with polyangiitis 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 [7]. 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 "Prognosis in granulomatosis with polyangiitis and microscopic polyangiitis, and management of those who develop end-stage renal disease".)

Pulse intravenous cyclophosphamide — Monthly intravenous pulses of cyclophosphamide have 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 with daily oral therapy is equivalent [22-26]. In almost all of these studies, 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 [22], after which long-term follow-up data (median of 4.3 years) were ascertained retrospectively on 134 patients [27]. During the trial, patients were treated with prednisolone and either pulse cyclophosphamide (15 mg/kg every two weeks for three doses and then every 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 during the trial phase [22]:

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 (eGFR) 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 with 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).

During a median of 4.3 years of follow-up, the following findings were noted [27]:

There was no difference in the number of deaths (13 in the intravenous pulse cyclophosphamide group and 12 in the daily oral group).

Significantly more patients in the intravenous pulse cyclophosphamide group had at least one relapse (40 versus 21 percent). The total number of relapses was significantly greater with intravenous pulse cyclophosphamide (54 versus 21 relapses).

Despite the higher relapse rate, there was no difference in the incidence of end-stage renal disease (13 versus 11 percent), and the median serum creatinine in the two groups at last follow-up was identical (1.32 mg/dL [117 micromol/L]).

These results are consistent with a prior meta-analysis that included 143 patients from three small randomized trials [26]. 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 as well as a trend toward a higher rate of relapse.

Intravenous cyclophosphamide dosing — If intravenous cyclophosphamide is selected, some experts use the regimen employed in the CYCLOPS trial (15 mg/kg every two weeks for three doses and then every three weeks for three to six months), while other experts treat with 0.5 g/m2 every two weeks for three to six months. If the white blood cell and absolute neutrophil count at two weeks are well above 3500/microL and 1000/microL, respectively, we increase the next dose to 0.75 g/m2 and, after repeating these labs two weeks later, reevaluate the need for a dose reduction back to 0.5 g/m2.

When using intermittent pulses of cyclophosphamide, some clinicians concomitantly administer mercaptoethane sulfonate (MESNA) to prevent cystitis, although the efficacy of this approach is unproven [34].

Patients receiving intravenous cyclophosphamide should also receive glucocorticoids. The regimen is discussed below. (See 'Glucocorticoid dosing' below.)

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

Summarized briefly, a report from the University of North Carolina (UNC) defined treatment resistance as one or both of the following despite immunosuppressive therapy for at least one month [8]:

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 scarring rather than ongoing inflammation and may respond best to local therapies such as triamcinolone injections and dilation procedures (avoiding laser therapies). (See 'Management of upper airway involvement' below.)

Contraindications to or refusal of 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 [18,19]. (See 'Rituximab-based regimen' below.)

Rituximab-based regimen — If a rituximab-based regimen is selected, we use the dose that was used in the RAVE trial, specifically 375 mg/m2 per week for four weeks. Some investigators use an alternative regimen, administering 1 g of rituximab initially followed 14 days later by another 1 g dose.

Patients receiving rituximab should also receive glucocorticoids. The regimen is discussed below. (See 'Glucocorticoid dosing' below.)

Glucocorticoid dosing — 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 1 or from day 4 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 [28,35]. Historically, the total duration of prednisone therapy has been six to nine months unless needed for control of persistent systemic symptoms. However, the use of glucocorticoids beyond six months may be associated with a significantly higher incidence of infections, and the utility of longer-term, low-dose glucocorticoids to reduce the risk of relapse is controversial [36,37]. Thus, unless required for resistant disease, we suggest tapering glucocorticoids by four to six months. Alternate-day glucocorticoid regimens, once recommended in GPA, are not generally employed now.

Combination cyclophosphamide and rituximab — Several observational studies and one small trial have reported results with the use of glucocorticoids, cyclophosphamide, and rituximab for initial therapy in patients with organ-threatening or life-threatening GPA or MPA [19,21,38,39]. In the RITUXVAS trial mentioned above, patients with newly diagnosed ANCA-associated renal vasculitis were assigned to receive glucocorticoids plus either rituximab in combination with two or three intravenous cyclophosphamide pulses or intravenous cyclophosphamide [19,21]. There were no differences between the groups in the rates of sustained remission, end-stage renal disease, or death.

A single-center observational study examined the outcomes of 120 patients with GPA or MPA treated with rituximab, including 20 who did not receive cyclophosphamide, 45 who had prior exposure to cyclophosphamide, and 55 who received both drugs concurrently [39]. Compared with those who received rituximab without concurrent cyclophosphamide, patients who were given both drugs simultaneously had similar remission rates, a nonsignificantly longer duration of sustained remission, and a nonsignificantly higher mortality.

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 have one or more of the following (algorithm 1) [30,40-46]:

Severe active renal disease – Patients who have rapidly deteriorating kidney function or severe kidney dysfunction (eg, those who have a serum creatinine above 4.0 mg/dL [354 micromol/L] or who require dialysis). (See 'Severe active renal disease' below.)

Concurrent anti-GBM autoantibody disease – Patients who have a positive anti-GBM autoantibody. (See 'Concurrent anti-GBM autoantibodies' below.)

Patients who have pulmonary hemorrhage – Some contributors to this topic would treat all patients who have pulmonary hemorrhage with plasma exchange, while others would use plasma exchange in only those patients with who also have severe respiratory impairment (eg, dyspnea or hypoxia) or if the patient does not respond quickly to therapy with intravenous glucocorticoids. (See 'Pulmonary hemorrhage' below.)

Rituximab may be removed from the body by plasma exchange. Thus, in such patients who are prescribed both rituximab and plasma exchange, one approach is to commence plasma exchange 48 hours after the initial dose of rituximab, and then to give the second dose of rituximab after plasma exchange has completed.

Severe active renal disease — Several 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 [40]. There was no difference in outcome according to the severity of serum creatinine elevations among patients not requiring dialysis. By 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 [46]. 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. All patients were given cyclophosphamide and oral glucocorticoids and were randomly assigned to receive either plasma exchange or intravenous methylprednisolone.

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 also reduced the risk of progression to end-stage renal disease at one year (19 versus 43 percent) [46] and nonsignificantly reduced progression at four years (33 versus 49 percent) [47]. Mortality was high in both groups at one year (27 and 24 percent) and was equivalent at four years (51 percent in both groups).

In a meta-analysis of 387 patients from nine trials (of which MEPEX was by far the largest), the addition of plasma exchange to standard care decreased the pooled risk of end-stage renal disease or death (relative risk [RR] 0.8, 95% confidence interval [CI] 0.65-0.99) and of end-stage renal disease alone (RR 0.64, 95% CI 0.47-0.88) [48]. The serum creatinine of participants ranged from 3.2 to 13.5 mg/dL (283 to 1193 micromol/L).

Despite limitations of these studies, the results of the MEPEX trial and the subsequent meta-analysis support the notion that the addition of plasma exchange to immunosuppressive therapy may enhance the recovery of renal function among patients who present with severe renal dysfunction (including those with rapidly deteriorating kidney function, even if the serum creatinine is not yet substantially elevated and the patient does not yet require dialysis). The ongoing PEXIVAS trial should provide further clarity on the usefulness of plasma exchange in these patients.

For patients with severe renal disease without concurrent anti-GBM autoantibody 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 risk of bleeding or a recent biopsy, we suggest that 1 to 2 liters of fresh frozen plasma be substituted for albumin at the end of the procedure to reverse pheresis-induced depletion of coagulation factors. For patients with active hemorrhage, the replacement fluid should exclusively be fresh frozen plasma.

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 autoantibodies — Based entirely upon presumed benefits in patients with anti-glomerular basement membrane (anti-GBM) autoantibody disease alone, plasma exchange is usually used in combination with immunosuppressive therapy in patients with ANCA-associated vasculitis who also have anti-GBM autoantibodies [49,50]. (See "Treatment of anti-GBM antibody (Goodpasture's) disease", section on 'Plasmapheresis' and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Anti-GBM autoantibody disease'.)

Pulmonary hemorrhage — All patients with pulmonary hemorrhage should be treated with pulse methylprednisolone plus either cyclophosphamide or rituximab. In addition, some contributors to this topic would treat all such patients with plasma exchange, while others would use plasma exchange in only those patients who also have severe respiratory impairment (eg, dyspnea or hypoxia) or if the patient does not respond quickly to therapy with intravenous glucocorticoids [50,51].

This use of plasma exchange in patients with GPA or MPA who have pulmonary hemorrhage is based upon the theoretical benefit of removing ANCA and the observed efficacy of plasma exchange in patients with pulmonary hemorrhage due to anti-GBM autoantibody disease.

However, the use of plasma exchange for treatment of alveolar hemorrhage is controversial. There is a wide spectrum of severity among patients presenting with pulmonary hemorrhage in the setting of ANCA-associated vasculitis. Some patients have mild involvement with little or no clinically detectable pulmonary impairment; conversely, other patients present with respiratory failure. This spectrum may be due to the identification of patients at varying stages of pulmonary hemorrhage. Thus, although all patients with pulmonary hemorrhage need prompt immunosuppressive therapy (pulse methylprednisolone plus either cyclophosphamide or rituximab), many patients do well without the addition of plasma exchange.

If plasma exchange is used, we suggest seven sessions over two weeks (60 mL/kg at each session). Fresh frozen plasma is the preferred 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.

The ongoing PEXIVAS trial should provide further clarity on the usefulness of plasma exchange in patients with severe GPA or MPA. However, at present, there are no published randomized, controlled trials. Benefits from plasma exchange in patients with ANCA-associated vasculitis and pulmonary hemorrhage were suggested by a retrospective review of 20 patients who presented between 1995 and 2001 with diffuse alveolar hemorrhage (DAH) and ANCA-associated small-vessel vasculitis [51]. 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 alternate-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 small size, retrospective design, lack of a control group, and single-center setting. 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.

Methotrexate in non-organ- and non-life-threatening disease — 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 (eg, patients with rhinosinusitis, arthritis, and/or pulmonary nodules with no other major organ involvement) [35,52-56] and, as discussed elsewhere, as maintenance therapy in patients treated initially with cyclophosphamide or 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 of 1 mg/dL [85 micromol/L] and microscopic hematuria in only 28 percent); the majority of patients had upper respiratory tract involvement [54]. The trial enrolled 89 patients with newly diagnosed GPA and six patients 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.

Methotrexate was also used for induction of remission among patients with nonsevere disease enrolled in WGET; remission rates with methotrexate were similarly high in this subset of patients with GPA [28].

Thus, methotrexate was as effective as cyclophosphamide for the induction of remission in patients with non-organ-threatening and non-life-threatening disease but was associated with a significantly higher relapse rate. The 2016 European League Against Rheumatism (EULAR) guidelines and the 2013 Kidney Disease Outcomes Quality Initiative (KDOQI) 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 extrarenal ANCA-associated vasculitis [13,15]. 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 non-organ-threatening and non-life-threatening 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 eGFR is below 50 mL/min per 1.73 m2. (See "Major side effects of low-dose methotrexate".)

Treatment-associated toxicity — Cyclophosphamide, rituximab, and glucocorticoids are all associated with important toxicity, and they do 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 diseases".)

Adverse effects of these drugs are discussed in separate topics:

Cyclophosphamide (see "General toxicity of cyclophosphamide in rheumatic diseases")

Rituximab (see "Rituximab and other B cell targeted therapies for rheumatoid arthritis" and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab')

Glucocorticoids (see "Major side effects of systemic glucocorticoids")

Prophylaxis against infection — Patients treated with immunosuppressive therapy for GPA or MPA are at high risk for infections [57,58]. In one large study, for example, the cumulative incidence of infection was 51 percent during the first year of treatment [57]. Most infections involved the respiratory tract, and most positive cultures revealed Staphylococcus aureus. By contrast, only one patient developed Pneumocystis carinii (jirovecii) pneumonia (PCP).

Without prophylaxis, PCP and other opportunistic infections can occur and are potentially fatal complications of immunosuppressive therapy in GPA or MPA. In one series, for example, PCP developed in 11 of 180 patients (6 percent) with GPA, all of whom were treated with daily glucocorticoids and a second immunosuppressive drug [59]. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in HIV-uninfected patients".)

Prophylaxis may be both cost saving and life prolonging in this setting. We typically administer prophylaxis to all patients initiating immunosuppressive therapy. Most commonly, we use trimethoprim-sulfamethoxazole (one single-strength [80 mg/400 mg] tablet daily or one double-strength tablet [160 mg/800 mg] three times per week). However, protocols for prophylaxis against infections vary among centers. (See "Treatment and prevention of Pneumocystis pneumonia in HIV-uninfected patients".)

Prophylaxis can be discontinued when the prednisone dose is 10 mg per day or less and, in patients who received cyclophosphamide for induction, when the cyclophosphamide dose has been discontinued.

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 antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, particularly in granulomatosis with polyangiitis (GPA). It is often difficult to determine whether 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 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 1 quart of water with 1 teaspoon of brine or pickling salt and 1 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. Clinicians should have a low threshold for referring patients with any signs or symptoms of suspected subglottic stenosis (eg, stridor, hoarseness, or unexplained dyspnea) to an otolaryngologist familiar with this problem. 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 [60,61].

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 three could not be decannulated [62]. (See "Clinical presentation, diagnostic evaluation, and management of central airway obstruction in adults".)

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 normal-appearing nose [63]. 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 granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), although both newly diagnosed and relapsing GPA and MPA can occur during pregnancy or in the postpartum period [64,65]. 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 or rituximab, or possibly other agents.

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 methotrexate and mycophenolate. In addition, there are insufficient data to assess the safety of rituximab in pregnancy. (See "Treatment-resistant granulomatosis with polyangiitis and microscopic polyangiitis", section on 'Mycophenolate mofetil in cyclophosphamide- and rituximab-resistant patients' 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 lesser 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 in rheumatic diseases", section on 'Teratogenicity'.)

Methotrexate is an abortifacient and teratogenic agent and is therefore contraindicated during pregnancy. (See "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Methotrexate'.)

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, but such an approach may necessitate prolonged use of high-dose glucocorticoids and a slower glucocorticoid taper. Alternatives that could be considered include cyclophosphamide or rituximab in the second or third trimester once organogenesis is complete.

The ongoing Vasculitis Pregnancy Registry (V-PREG) study is collecting data on maternal and fetal outcomes in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (and other vasculitides) in order to provide informed guidance to patients and clinicians on the management of vasculitis during pregnancy.

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

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults" and "Society guideline links: Vasculitis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Granulomatosis with polyangiitis (The Basics)")

Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are related systemic vasculitides that, along with eosinophilic granulomatosis with polyangiitis (Churg-Strauss), make up the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides. Both GPA and MPA are associated with ANCA, have many identical clinical manifestations, have many similar histologic features, and have similar outcomes. Therapy for GPA and MPA has two main components: induction of remission with initial immunosuppressive therapy, and maintenance of remission with immunosuppressive therapy for a variable period to prevent relapse. (See 'Introduction' above.)

Immunosuppressive therapy is warranted in almost all patients with active GPA or MPA. Induction of complete remission is the goal and expectation of treatment with immunosuppressive therapy in GPA or MPA and is defined as the absence of active disease (ie, the absence of any clinical manifestations that are deemed secondary to ongoing active vasculitis). It is important but sometimes difficult to differentiate evidence of active vasculitis from permanent damage, which can be due either to the underlying disease or to its treatment. Complete remission does not mean that all parameters have to return to baseline. Many patients have persistent abnormalities that reflect irreversible injury induced during the period of active inflammation, for example, chronic upper airway mucosal damage with nasal crusting or a residual lung nodule (scar), chronic but stable peripheral neuropathic sensory changes, and persistent proteinuria and renal insufficiency. (See 'General principles' above.)

Initial immunosuppressive therapy in GPA and MPA typically consists of glucocorticoids combined with either cyclophosphamide or rituximab. Selected patients with severe disease may benefit from the addition of plasma exchange. 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. (See 'Initial therapy' above.)

Our approach to initial therapy depends upon the severity of the disease and the organ systems involved (algorithm 1) (see 'Overall approach to initial therapy' above):

Non-organ-threatening and non-life-threatening disease – This group of patients has no evidence for "active" glomerulonephritis (ie, normal serum creatinine and no red cell casts or proteinuria) and no organ-threatening or life-threatening manifestations (eg, absence of pulmonary hemorrhage, cerebral vasculitis, progressive neuropathy, orbital pseudotumor, gastrointestinal bleeding, pericarditis, or myocarditis). Such patients may have rhinosinusitis, arthritis, and/or pulmonary nodules. Non-organ-threatening and non-life-threatening disease can still result in substantial disease burden and long-term damage.

Organ-threatening or life-threatening disease – Other patients with GPA or MPA are classified into this group for the purpose of initial therapy. Such patients may have manifestations including (but not limited to) marked pulmonary hemorrhage, rapidly deteriorating renal function, or motor neuropathy.

Based upon these groups of disease severity, our therapeutic approach is as follows (algorithm 1):

Non-organ-threatening and non-life-threatening disease – In these patients, we suggest a regimen of glucocorticoids in combination with methotrexate (Grade 2C). Initial treatment of nonsevere disease with rituximab is also reasonable, especially if there is a contraindication to methotrexate use. Those who are treated with methotrexate and who do not respond or who have progressive disease should be treated with either cyclophosphamide or rituximab.

Organ-threatening or life-threatening disease – The authors and editors of this topic do not agree on the preferred initial immunosuppressive regimen in such patients. Overall, we recommend a regimen consisting of glucocorticoids in combination with either cyclophosphamide (oral or intravenous) or rituximab, rather than other immunosuppressive regimens (such as glucocorticoid monotherapy or methotrexate) (Grade 1A). Some authors/editors favor a cyclophosphamide-based regimen as initial therapy, while others choose a rituximab-based regimen for the majority of patients.

Also, we suggest plasma exchange in addition to glucocorticoids and either cyclophosphamide or rituximab in patients with GPA or MPA who have one or more of the following features (algorithm 1) (Grade 2C) (see 'Role of plasma exchange' above):

-Patients who have rapidly deteriorating kidney function or severe kidney dysfunction (eg, those who have a serum creatinine above 4.0 mg/dL [354 micromol/L] or who require dialysis).

-Patients who have pulmonary hemorrhage – Some contributors to this topic would treat all patients who have pulmonary hemorrhage with plasma exchange, while others would use plasma exchange in only those patients who also have severe respiratory impairment (eg, dyspnea or hypoxia) or if the patient does not respond quickly to therapy with intravenous glucocorticoids.

-Patients who have a concomitantly positive anti-glomerular basement membrane (anti-GBM) autoantibody.

Details of cyclophosphamide-based regimens, cyclophosphamide resistance, and contraindications to cyclophosphamide are discussed above; the adverse effects associated with cyclophosphamide therapy are presented elsewhere. (See 'Cyclophosphamide-based regimen' above and "General toxicity of cyclophosphamide in rheumatic diseases".)

Details of rituximab-based regimens are discussed above; the adverse effects associated with rituximab therapy are presented elsewhere. (See 'Rituximab-based regimen' above and "Rituximab and other B cell targeted therapies for rheumatoid arthritis" and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab'.)

Glucocorticoids are given in combination with cyclophosphamide or rituximab. 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. Prolonged glucocorticoid monotherapy should not be used. Dosing of glucocorticoids is discussed above. (See 'Glucocorticoid dosing' above.)

The use of methotrexate in non-organ-threatening and non-life-threatening disease is discussed above. (See 'Methotrexate in non-organ- and non-life-threatening disease' above.)

In addition, we administer prophylaxis against opportunistic infections during induction therapy. Most commonly, we use trimethoprim-sulfamethoxazole (one single-strength [80 mg/400 mg] tablet daily or one double-strength tablet [160 mg/800 mg] three times per week). However, protocols for prophylaxis against infections vary among centers. (See 'Prophylaxis against infection' above.)

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, particularly in GPA. It is often difficult to determine whether 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 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. Clinicians should have a low threshold for referring patients with any signs or symptoms of suspected subglottic stenosis (eg, stridor, hoarseness, or unexplained dyspnea) to an otolaryngologist familiar with this problem. (See 'Management of upper airway involvement' above.)

There is only limited information on pregnancy complicated by GPA and MPA, although both newly diagnosed and relapsing disease can occur during pregnancy or in the postpartum period. As with active disease in nonpregnant patients, prednisone alone is relatively ineffective, particularly for moderate to severe disease. 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 methotrexate and mycophenolate. In addition, there are insufficient data to assess the safety of rituximab in pregnancy. As a result, there are three major therapeutic approaches in women with significant active disease during pregnancy: the use of immunosuppressive drugs that are safer in pregnancy (eg, glucocorticoids, azathioprine, and calcineurin inhibitors); therapeutic abortion prior to initiation of cyclophosphamide-based therapy; or the use of rituximab, which has insufficient safety data for use in pregnancy. (See 'Management in pregnancy' above.)

ACKNOWLEDGMENT — UpToDate would like to thank Dr. John Stone, who contributed to earlier versions of this topic review.

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