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 may have similar outcomes. There is, however, substantial heterogeneity among these disorders. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)
Therapy for GPA and MPA has two main components: induction of remission with immunosuppressive therapy and maintenance of remission with immunosuppressive therapy for a variable period to prevent relapse.
Induction and maintenance therapy of GPA and MPA will be reviewed here. The clinical manifestations and diagnosis of these disorders and the treatment of resistant and relapsing disease are discussed elsewhere:
Goals of therapy — The goal of therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is to achieve long-standing remission. Treatment consists of an initial induction phase aimed to put patients with active disease into remission, followed by a maintenance phase that is intended to extend remission and prevent relapse.
Definitions of response
●Complete remission – Complete remission is defined as the absence of active disease (ie, the absence of any clinical manifestations that are deemed secondary to ongoing active vasculitis) [1-5]. Complete remission does not mean that all parameters have returned to baseline, because persistent abnormalities may reflect irreversible injury induced during the period of active inflammation. As an example, a patient in whom the systemic symptoms and signs resolve and the urine sediment becomes inactive is considered to be in remission, even if there is persistent proteinuria or persistent or even slowly worsening kidney function impairment.
●Partial remission – Partial remission is more difficult to define but implies the persistence of some inflammation despite immunosuppressive therapies. Defining and characterizing the impact of "partial remission" is further complicated by recognition that some clinical trials in GPA and MPA defined a state of remission as including patients with a single item of nonsevere disease activity .
•Distinguishing partial remission from other disease states – Partial remission (ie, ongoing low-level inflammation) may be difficult to distinguish from other processes that result in persistent symptoms, such as organ damage from prior inflammation and chronic infection. The distinction may be particularly challenging for disease affecting the sinuses and respiratory tract. As an example, 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 "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of disease resistant to initial therapy", section on 'Exclusion of alternative diagnoses'.)
In the kidneys, as in other inflammatory glomerular diseases such as lupus nephritis, persistent proteinuria (as determined by urine dipstick) could reflect either ongoing inflammation or irreversible glomerular injury and thus, as an isolated finding, is not necessarily indicative of active disease . Similarly, isomorphic hematuria, which is characteristic of extraglomerular bleeding, could reflect cyclophosphamide-induced bladder toxicity. (See "Etiology and evaluation of hematuria in adults", section on 'Red cell morphology'.)
•Partial remission inadequate as treatment goal – Partial remission may not be an adequate goal for therapy. In a retrospective study of 167 patients with GPA or MPA who were followed for five years, achieving a low disease activity state (defined as a Birmingham Vasculitis Activity Score ≤3 and use of prednisone ≤7.5 mg daily) was associated with more organ damage than prolonged complete remission (Vasculitis Damage Index score 3.7 versus 2.2) . However, there is no consensus definition of low disease activity state in GPA or MPA. Thus, while partial remission is clearly better than no remission, it should not be the ultimate goal of successful treatment.
Persistent dysmorphic (ie, glomerular) hematuria (picture 1A-B) may be evidence of incomplete remission in patients who have a stable serum creatinine and no other evidence of disease activity. Patients with this finding may require additional therapy to prevent progressive kidney injury and should be followed more closely with thoughts of a potential biopsy. (See "Etiology and evaluation of hematuria in adults", section on 'Red cell morphology'.)
●Relapse – Relapse is defined as the recurrence of signs or symptoms of active vasculitis in any organ system after remission is achieved. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease".)
INITIAL TREATMENT APPROACH — Immunosuppressive therapy is warranted in almost all patients with active granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). The choice of therapy is discussed below.
Our management strategy is generally consistent with guidelines developed by professional organizations including the American College of Rheumatology (ACR)/Vasculitis Foundation  and Kidney Disease: Improving Global Outcomes (KDIGO) .
Assessment of disease severity — Our approach to initial therapy depends largely upon the severity of disease and the organ systems involved. Other factors that may influence initial choice of therapy include patient-specific factors.
●Organ-threatening or life-threatening disease – Organ- or life-threatening features include, but are not limited to, the following (see 'Organ- or life-threatening disease' below):
•Progressive peripheral or cranial neuropathy
•Gastrointestinal bleeding due to vasculitis
•Cardiac disease due to vasculitis (pericarditis, myocarditis)
●Non-organ-threatening and non-life-threatening disease – Patients with non-organ- or non-life-threatening disease have no evidence of "active glomerulonephritis" (ie, normal serum creatinine and no red cell casts or proteinuria) and none of the organ-threatening or life-threatening manifestations listed above. 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. (See 'Non-organ- and non-life-threatening disease' below.)
Organ- or life-threatening disease
Induction therapy — In patients with GPA or MPA who have organ- or life-threatening disease, we recommend an induction regimen consisting of glucocorticoids in combination with either rituximab or cyclophosphamide rather than monotherapy with glucocorticoids. Some authors/editors choose a rituximab-based regimen for the majority of patients, given its comparable efficacy and different side-effect profile compared with cyclophosphamide . Other authors/editors favor a cyclophosphamide-based regimen as initial therapy, particularly in patients presenting with more severe kidney disease and/or pulmonary hemorrhage, or if rituximab is difficult to access . In patients with concerns about fertility, alopecia, and malignancy or those who have been previously treated with a course of cyclophosphamide; in children; and in frail older adults, some prefer rituximab as the initial therapy (algorithm 1) . Some authorities treat with glucocorticoids in combination with both rituximab and cyclophosphamide. However, no trials have shown that this approach is superior to the use of either cyclophosphamide or rituximab as initial therapy.
Prior to the introduction of cyclophosphamide as a therapy for GPA or MPA, the majority of patients were treated with glucocorticoid monotherapy, but mortality rates with this therapy were high [2,13]. Observational studies found that the combination of cyclophosphamide plus glucocorticoids as induction therapy was associated with more than a fivefold improvement in survival and a lower frequency of relapse [3,14]. The combination of oral cyclophosphamide and glucocorticoids ultimately induces remission in 75 to 90 percent of patients, with approximately 50 to 70 percent experiencing complete remission by six months [2,3,15-17]. Most remissions occur between three and six months of induction therapy [15,18].
There are two seminal randomized trials that have suggested that rituximab is an effective alternative to cyclophosphamide for the initial treatment of patients who have newly diagnosed disease or relapsed following treatment with cyclophosphamide or other immunosuppressive therapy:
●The Rituximab for ANCA-Associated Vasculitis (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 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 . All patients received one to three pulses of methylprednisolone (1000 mg) followed by prednisone (1 mg/kg per day). At six months, induction of remission rates in rituximab-treated patients were similar to those treated with cyclophosphamide (64 versus 53 percent, respectively). In addition, in the 100 patients with relapsing disease, rituximab was superior to cyclophosphamide in inducing remission (67 versus 42 percent) at six months. The rates of adverse events were similar between the two groups.
Of the 197 patients initially enrolled in RAVE, the 146 patients who achieved complete remission were followed through month 18 . 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, the number of deaths or the rate of severe infections was similar between the treatment groups.
●In a smaller trial (Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis [RITUXVAS]), 44 patients with newly diagnosed antineutrophil cytoplasmic autoantibody (ANCA)-associated renal vasculitis were assigned in a 3:1 ratio to receive intravenous (IV) 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 IV cyclophosphamide pulses (15 mg/kg) or IV cyclophosphamide (15 mg/kg every two weeks for three doses followed by infusions every three weeks) for three to six months followed by azathioprine [21,22]. At 12 and 24 months in RITUXVAS, the rate of sustained remission (defined as the absence of disease activity for at least six months) was similar between the rituximab/cyclophosphamide and cyclophosphamide-only groups (76 versus 82 percent). The rate of adverse events at 12 months was also similar between the two groups.
An important consideration when reviewing both of these trials is that patients with alveolar hemorrhage requiring mechanical ventilation or with serum creatinine levels >4 mg/dL were excluded from enrollment in the RAVE trial. However, some of the patients in RAVE went on to require mechanical ventilation or had serum creatinine levels >4 mg/dL after enrollment. Thus, there is still some uncertainty about the efficacy of rituximab in this population, although there are also no randomized trial data to support the use of cyclophosphamide in such situations. In a post hoc analysis of 102 patients in the RAVE trial who had kidney involvement at enrollment, of which 62 had an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, rates of remission were similar between the treatment groups . Although RITUXVAS did include a small number of patients with kidney failure requiring dialysis, patients also received cyclophosphamide initially as part of the trial design.
Although few patients over the age of 75 were included in the two aforementioned trials, rituximab appears to be effective in this patient population. In an observational study that included 66 adults aged >75 years with GPA or MPA who received induction therapy with rituximab, 57 (86 percent) achieved remission and two (3 percent) experienced relapse . However, rates of serious infection were high (46.6 per 100 patient-years). (See 'Older patients' below.)
It remains uncertain whether the ANCA serotype (ie, proteinase 3 [PR3]-ANCA versus myeloperoxidase [MPO]-ANCA positivity) affects the response to the specific induction regimen. A post hoc analysis of the RAVE trial found that patients who were PR3-ANCA positive and received rituximab were more likely to achieve remission at six months compared with those treated with cyclophosphamide and azathioprine (65 versus 48 percent, respectively; odds ratio 2.11, 95% CI 1.04-4.30). Although this difference was not observed at 12 or 18 months, it should be noted that the patients treated with rituximab received no maintenance therapy while those treated with cyclophosphamide subsequently received azathioprine up to month 18 , and these results have not been validated in an independent dataset. No association between treatment and remission was observed in the patients who were MPO-ANCA positive.
Rituximab-based regimen — If a rituximab-based regimen is selected, either the dose regimen used for rheumatoid arthritis (administering 1 g of rituximab followed 14 days later by another 1 g dose) or the dosing regimen that was used in the RAVE trial (375 mg/m2 per week for four weeks) can be used. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Initial dose'.)
Several anti-CD20 drugs other than rituximab are available, but none have yet to be studied comprehensively in patients with ANCA-associated vasculitis. However, in a small series of three patients with ANCA-associated vasculitis and a history of anaphylaxis to rituximab, obinutuzumab (an anti-CD20 antibody) appeared to be efficacious and a reasonable alternative .
Cyclophosphamide-based regimen — If a cyclophosphamide-based regimen is selected, the choice of oral versus IV cyclophosphamide is largely dictated by practice style. Both oral and IV regimens are highly effective. Some clinicians prefer IV cyclophosphamide given the lower cumulative dose associated with this administration and theoretical subsequent lower risk of toxicity. After approximately three to six months, cyclophosphamide is replaced by a medication with a lower risk of toxicity. (See 'Choice of maintenance therapy' below.)
●IV cyclophosphamide dosing – If IV 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) , with appropriate dose reductions made in older adults and patients with impaired kidney function. As an example, the cyclophosphamide dose can be reduced by 2.5 mg/kg per pulse for patients age 60 to 70 years and by 5 mg/kg per pulse for patients older than 70 years . We usually reduce the dose by one-half (ie, from 15 mg/kg to 7.5 mg/kg per pulse) in patients with an eGFR <30 mL/min/1.73 m2. 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 above 3500/microL and 1500/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. A more detailed discussion of dosing, dose adjustments, adverse effects, and the use of MESNA is presented elsewhere. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Intermittent (pulse) cyclophosphamide'.)
●Oral cyclophosphamide dosing – If oral cyclophosphamide is used, it is typically given in a dose of 1.5 to 2 mg/kg per day, with appropriate dose reductions made in older adults and patients with impaired kidney function (table 1). 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.
Randomized trials comparing daily oral and monthly IV cyclophosphamide regimens have shown that the rate of induction of remission is almost equivalent [15,16,27-29]. In almost all of these studies, IV therapy had the advantages of lower total cyclophosphamide exposure and lower rates of neutropenia and infection but a trend toward a higher rate of relapse. As an example, a randomized trial (CYCLOPS) including 149 patients with ANCA-associated vasculitis 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) found 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. 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 IV 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 lower cumulative cyclophosphamide dose and a lower rate of leukopenia. During a median of 4.3 years of follow-up, more patients in the IV pulse cyclophosphamide group relapsed, but the incidence of end-stage kidney disease (ESKD) was similar .
Glucocorticoid dosing and taper — Oral glucocorticoid therapy is typically started at 1 mg/kg per day (maximum of 60 to 80 mg/day of oral prednisone or its equivalent) for most patients with organ- or life-threatening disease. High-dose IV ("pulse") glucocorticoids (such as methylprednisone 7 to 15 mg/kg to a maximum dose of 1000 mg/day for three days) are usually limited to patients presenting with manifestations such as rapidly progressive glomerulonephritis, pulmonary hemorrhage, mononeuritis multiplex, or optic neuritis. Daily oral glucocorticoids are then started after the IV therapy.
For most patients with GPA or MPA receiving glucocorticoids in combination with a glucocorticoid-sparing agent, we recommend a reduced-dose glucocorticoid tapering regimen rather than the standard-dosing taper. A variety of reduced-dose prednisone tapering schemes have been employed. As an example, if the initial dose of prednisone is 60 mg/day, it can be reduced by 50 percent to 30 mg in one to two weeks (table 2). Unless higher doses are required for resistant or relapsing disease, prednisone should be tapered to 5 mg daily or discontinued by four to six months. Concomitant treatment with avacopan may facilitate the use of an even shorter, reduced-dose glucocorticoid regimen, as discussed below. (See 'Avacopan' below.)
The use of a reduced-dose glucocorticoid tapering regimen is based upon data from randomized trials demonstrating that patients who receive such a regimen have similar rates of remission compared with those who receive standard-dosing regimens, while experiencing fewer adverse effects [31-33]:
●In the Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody (ANCA)-Associated Vasculitis (PEXIVAS) trial that included 704 patients with newly diagnosed or relapsing severe GPA or MPA, a reduced-dose oral glucocorticoid regimen resulted in similar rates of ESKD and death compared with a standard-dose glucocorticoid regimen and was also associated with fewer serious infections at one year . Serious infections occurred in 96 patients (27 percent) in the reduced-dose glucocorticoid regimen compared with 180 patients (33 percent) in the standard-dose regimen (incidence rate ratio, 0.69 [95% CI 0.52-0.93]).
●In a second trial that randomly assigned 140 patients with newly diagnosed MPA or GPA (without severe glomerulonephritis or alveolar hemorrhage) to rituximab plus either reduced-dose (0.5 mg/kg/day) or standard-dose (1 mg/kg/day) prednisolone, rates of remission at six months were comparable between the groups (71 versus 69 percent, respectively) . Rates of serious adverse events were lower in the reduced-dose group (19 versus 37 percent), as were serious infections (7 versus 20 percent).
Role of plasma exchange — The authors/editors of this topic do not fully agree on the extent of the role of plasma exchange, in addition to glucocorticoids and either cyclophosphamide or rituximab, among patients with GPA or MPA:
●Double-positive anti-GBM and ANCA-associated disease – All authors agree with the use of plasma exchange for most patients with GPA or MPA who are concomitantly positive for anti-glomerular basement membrane (anti-GBM) autoantibody [9,11,12]. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis", section on 'Plasmapheresis plus immunosuppressive therapy'.)
●Severe kidney disease – When to use plasma exchange to treat patients with GPA or MPA and severe active kidney disease is controversial. Some experts institute plasma exchange immediately upon identification of severe kidney disease (eg, serum creatinine >4.0 mg/dL [354 micromol/L] or need for dialysis) while others first consider the response to initial immunosuppressive therapy. The extent to which kidney biopsy findings influence this decision is an area of ongoing interest , and some authors suggest that the presence of active inflammation without significant glomerulosclerosis identifies patients most likely to benefit from plasma exchange.
●Pulmonary hemorrhage – Some other authors would also offer plasma exchange to patients with GPA or MPA who present with pulmonary hemorrhage, while other authors would reserve the use of plasma exchange for patients with pulmonary hemorrhage not readily responding to other therapies and optimal supportive care.
If plasma exchange is used, we suggest seven sessions over two weeks (60 mL/kg at each session). Albumin is the preferred replacement fluid in patients without bleeding or a recent kidney 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 IV immune globulin (100 to 400 mg/kg) can be given to partially replenish antibody levels.
The rationale for limiting the use of plasma exchange is largely based upon data from the PEXIVAS randomized trial of 704 patients with newly diagnosed or relapsing severe GPA or MPA (defined by an eGFR <50 mL/min/1.73 m2 or diffuse pulmonary hemorrhage), in which the use of plasma exchange did not reduce the incidence of death or ESKD (hazard ratio [HR] 0.86, 95% CI 0.65-1.13) at one year or during the follow-up period of up to seven years . At baseline, the median serum creatinine level was 3.7 mg/dL (327 micromol/L) and approximately 20 percent of patients required dialysis; approximately 18 percent of patients had pulmonary hemorrhage, less than one-half of whom had severe hemorrhage. All patients received either cyclophosphamide or rituximab, the majority of whom received cyclophosphamide (85 percent). Patients were also randomly assigned to either a standard-dose or reduced-dose glucocorticoid regimen, which is discussed above. (See 'Glucocorticoid dosing and taper' above.)
Evidence in support of the use of plasma exchange among patients with severe active kidney disease comes from small, randomized trials and meta-analyses that suggest that plasma exchange may improve short-term kidney outcomes but has no effect on mortality in this patient population [35-39]. A meta-analysis of randomized trials (including the PEXIVAS trial) suggested that plasma exchange, in addition to standard induction therapy, does not improve mortality and may increase the risk of serious infections but appears to reduce the risk of ESKD at 12 months (relative risk [RR] 0.62, 95% CI 0.39-0.98) . This benefit was greatest for patients at high risk of ESKD (defined as serum creatinine >5.7 mg/dL [500 micromol/L] or requiring dialysis; absolute risk reduction 16.0 percent, 95% CI 4.2-23.6 percent). However, in a retrospective review of 251 patients with ANCA-associated vasculitis who had severe kidney disease (eGFR <30 mL/min/1.73 m2), the addition of plasma exchange to standard therapy was not associated with a benefit on remission induction, the rate of ESKD and/or death at 18 months, progression to ESKD, or survival at 24 months .
There is more uncertainty regarding the efficacy of plasma exchange in patients with GPA or MPA and severe diffuse alveolar hemorrhage. Although the PEXIVAS trial did not demonstrate improved outcomes with plasma exchange, only a small proportion of the patients enrolled in this trial presented with severe hemorrhage . In addition, retrospective data regarding the effects of plasma exchange on diffuse alveolar hemorrhage have shown mixed results [41-45]. In one study of 73 patients with diffuse alveolar hemorrhage, of whom 34 required mechanical ventilation, the use of plasma exchange was not associated with achieving complete remission at six months . Another analysis of 11 studies including 172 patients with diffuse alveolar hemorrhage reported similar rates of resolution of diffuse alveolar hemorrhage and survival at hospital discharge among patients who received plasma exchange and those who did not .
The appropriate role of plasma exchange in treatment of GPA and MPA will continue to evolve as more structured combined analyses of the data to date are conducted and analyses of specific subpopulations (eg, pulmonary hemorrhage) become available. Our approach to the use of plasma exchange is generally consistent with the recommendations of the American College of Rheumatology/Vasculitis Foundation  and KDIGO .
Combination with ritixumab and cyclophosphamide — Some experts treat with glucocorticoids in combination with both rituximab and cyclophosphamide. However, this approach remains controversial, and there is no expert consensus as to which patients should receive the combination of rituximab and cyclophosphamide for induction of remission for GPA or MPA. This approach is based on several observational studies and limited trial data suggesting there may be a benefit in terms of lower exposure to glucocorticoids and lower infectious complications, while maintaining similar remission rates [21,22,46-50]. As examples:
●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 [21,22,46-50]. 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 IV cyclophosphamide pulses or IV cyclophosphamide alone [21,22]. There were no differences between the groups in the rates of sustained remission, ESKD, 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 65 who received both drugs prior to reaching a remission . Compared with those who received rituximab without cyclophosphamide, patients who were given both drugs concurrently had similar remission rates, a nonsignificantly longer duration of sustained remission, and a nonsignificantly higher mortality.
Avacopan — Some clinicians use the complement C5a receptor inhibitor avacopan as an adjunctive agent with standard induction therapy to limit the use of glucocorticoids. Avacopan is administered as 30 mg orally twice daily, typically in combination with a shorter, reduced-dose glucocorticoid regimen in which glucocorticoids are tapered over four to six weeks depending upon patient response. Use of avacopan should be avoided in patients with active, untreated, and/or uncontrolled chronic liver disease and patients who are taking moderate to strong CYP3A4 inducers; the dose should be reduced to 30 mg daily in patients who are taking strong CYP3A4 enzyme inhibitors (table 3).
The use of avacopan is supported by evidence from trials demonstrating disease remission with limited use of glucocorticoids [51-53]. In a trial including 331 patients with newly diagnosed or relapsing antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, patients were randomly assigned to receive either oral avacopan 30 mg twice daily or prednisone on a tapering schedule; all patients received standard remission-induction therapy with cyclophosphamide (followed by azathioprine) or rituximab . Approximately 80 percent of patients had kidney involvement. At 26 weeks, the rates of disease remission were similar between the two groups (72 percent in the avacopan group versus 70 percent in the prednisone group). At 52 weeks, sustained remission was higher in the avacopan group than in the prednisone group (66 versus 55 percent). The rate of overall serious adverse events (excluding worsening vasculitis) was similar for both regimens (37 versus 39 percent for avacopan and prednisone, respectively). Similar safety data have been found in a smaller trial of avacopan added to standard-of-care treatment for ANCA vasculitis . It should be noted that glucocorticoids were also used by some patients in the avacopan group in the first few weeks following initiation of treatment, but the mean total dose was approximately one-third of that in the prednisone group (1349 mg versus 3655 mg). In addition, patients in the avacopan group experienced less glucocorticoid-related toxicity than those in the prednisone group. The safety and efficacy of avacopan beyond 52 weeks have not yet been addressed.
Maintenance therapy — After attainment of remission with induction immunosuppressive therapy, almost all patients are switched to a maintenance regimen.
The authors and reviewers of this topic think that certain low-risk, newly diagnosed patients who were originally MPO-ANCA positive and have attained a complete remission may be safely followed without maintenance therapy. Since PR3-ANCA-positive patients as a group have a higher risk of relapse compared with MPO-ANCA-positive patients, the former are not included in this group. The selection of such MPO-ANCA-positive patients is individualized and is based upon whether the patient has risk factors for relapse (eg, the presence of lung or upper respiratory tract involvement prior to remission) or a tenuous clinical status (eg, an older individual with reduced glomerular filtration rate [GFR] is less likely to tolerate a relapse than a younger individual with normal GFR). If patients are managed without maintenance immunosuppression, they should be followed with frequent clinic visits, regular testing of serum creatinine, and weekly home urine dipsticks. (See 'Monitoring the response to therapy' below.)
When to start maintenance therapy — The combination of glucocorticoids plus either rituximab or oral or IV cyclophosphamide induces remission in the majority of patients, usually within three to six months after the initiation of therapy. Patients in whom remission or evidence of progressive improvement is not attained within six months should be considered to have disease resistant to the chosen induction regimen and have their treatment regimen altered. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of disease resistant to initial therapy".)
The timing of initiation of maintenance therapy depends upon the induction regimen used:
●For patients treated with rituximab for induction of remission, maintenance therapy typically begins between months four and six after the last induction dose, regardless of the maintenance agent that is used.
●For patients treated with IV cyclophosphamide for induction of remission, maintenance therapy is started two to four weeks after the last dose of cyclophosphamide if the following white blood cell criteria are met: The white blood cell count is >3500 cells/microL, and the absolute neutrophil count is >1500 cells/microL. When daily oral cyclophosphamide is used for induction of remission, maintenance therapy can be started as soon as the above white blood cell criteria are met. In some patients, maintenance therapy can be started the day after oral cyclophosphamide is stopped.
After approximately three to six months, cyclophosphamide is replaced by a medication with a lower risk of toxicity. This includes any of the alternatives discussed below. (See 'Choice of maintenance therapy' below.)
Choice of maintenance therapy — In patients who achieve remission after a new diagnosis of GPA or MPA, the choice of maintenance therapy is influenced by disease severity and patient-specific factors. In most patients who achieve remission after induction immunosuppressive therapy, we suggest treatment with rituximab for maintenance of remission. Azathioprine, methotrexate, and mycophenolate are reasonable alternatives and may be preferred based on other patient-specific factors. The choice of agent for patients with relapsing disease is discussed separately. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease".)
Examples of patient-specific factors that may influence the choice of the maintenance agent include a prior history of toxicity from a certain drug and/or a comorbid condition that increases the risk of toxicity with a specific agent.
●Given the risk of toxicity with use of methotrexate in patients with reduced kidney function, this drug should not be used in patients with an eGFR <60 mL/min/1.73 m2 or evidence of active renal vasculitis. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Conventional cytotoxic agents", section on 'Methotrexate' and "Major side effects of low-dose methotrexate".)
●Rituximab should be avoided, or used in conjunction with anti-hepatitis B virus (HBV) therapy, in patients who are positive for hepatitis B surface antigen (HBsAg) or antibodies to the hepatitis B core antigen (anti-HBc) due to the elevated risk of reactivation and potentially fatal hepatitis.
●Azathioprine is the preferred agent for maintenance therapy in patients who want to become pregnant since methotrexate is contraindicated in pregnancy and the risk of rituximab during gestation is not yet well characterized.
Dosing of drugs that are used for maintenance therapy is discussed below. (See 'Dosing of maintenance therapy' below.)
The major, well-designed, randomized trials that examined the efficacy of maintenance therapy in patients with GPA or MPA included newly diagnosed patients almost exclusively, rather than relapsed patients. These trials are summarized below:
●The Cyclophosphamide versus Azathioprine for Early Remission Phase of Vasculitis (CYCAZAREM) trial, which included 155 patients with newly diagnosed ANCA-positive vasculitis, found that the substitution of azathioprine after induction therapy with oral cyclophosphamide did not increase the rate of relapse . The 144 patients in whom remission was achieved (77 percent at three months and a further 16 percent between three and six months) were randomly assigned to either continued cyclophosphamide (1.5 mg/kg per day) or azathioprine (2 mg/kg per day) while remaining on prednisolone at 10 mg/day. After one year, both groups were treated with azathioprine (1.5 mg/kg per day) plus prednisolone (7.5 mg per day). At 18 months, the rates of relapse were similar between the azathioprine and cyclophosphamide groups (15.5 versus 13.7 percent), and, during the maintenance phase, both groups had a similar number of severe adverse events (eight and seven patients, respectively). However, cyclophosphamide is associated with serious malignancies over the long term and is no longer commonly used for maintenance therapy in patients with GPA or MPA. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Malignancy'.)
●The Wegener Granulomatosis-Entretien (WEGENT) trial found that azathioprine and methotrexate provide comparable efficacy and are similarly safe when administered for maintenance therapy . In this trial, 126 patients with newly diagnosed GPA or MPA who were in remission after treatment with cyclophosphamide and oral glucocorticoids were randomly assigned to azathioprine (2 mg/kg per day) or methotrexate for 12 months followed by gradual withdrawal over three months . The mean serum creatinine was approximately 2 mg/dL (176 micromol/L) at baseline and 1.5 mg/dL (129 micromol/L) at randomization. At a mean follow-up of 29 months, both drugs were associated with a similar number of adverse effects that required drug discontinuation (11 and 19 percent for azathioprine and methotrexate, respectively) and a similar relapse rate (36 and 33 percent). The majority of relapses (73 percent) occurred after the cessation of maintenance therapy.
●The best data supporting the use of rituximab as maintenance therapy come from the Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trial that compared rituximab with azathioprine in 115 patients who had attained remission after initial therapy using cyclophosphamide plus glucocorticoids; most patients were newly diagnosed rather than relapsed (80 versus 20 percent), had GPA rather than MPA (76 versus 20 percent), and had a positive PR3-ANCA rather than MPO-ANCA (70 versus 23 percent) . Rituximab was given as two 500 mg doses separated by 14 days at baseline and then again at months 6, 12, and 18. Azathioprine was given at a dose of 2 mg/kg per day for 12 months followed by 1.5 mg/kg per day for six months and then 1 mg/kg per day for four additional months. Treatment with rituximab produced a lower rate of major relapse as compared with azathioprine at 28 months (5 versus 29 percent). The number of serious adverse events was similar in both groups.
●The International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides (IMPROVE) trial was an open-label, randomized, multicenter trial that included 156 patients with newly diagnosed ANCA-associated vasculitis and found that azathioprine was more effective than mycophenolate for maintenance therapy . After induction of remission with cyclophosphamide and glucocorticoids, patients received either azathioprine (starting at 2 mg/kg per day and then reduced to 1.5 and 1 mg/kg per day after 12 and 18 months, respectively) or mycophenolate mofetil (starting at 2000 mg per day and then reduced to 1500 and 1000 mg per day after 12 and 18 months, respectively). Both agents were withdrawn after 42 months of treatment. At a median follow-up of 39 months, relapses were significantly less frequent among those who received azathioprine (38 versus 55 percent, adjusted HR 0.56, 95% CI 0.34-0.91). The rate of adverse events was not significantly higher for those who received azathioprine (16 versus 8 percent, respectively).
Data from observational studies and small trials also suggest that mycophenolate mofetil can maintain remission in patients with GPA or MPA [57-62]. As an example, in an open-label trial including 14 patients with GPA who received induction therapy with daily oral cyclophosphamide and prednisone and who were subsequently treated with mycophenolate mofetil (2 g/day), six patients (43 percent) relapsed at a median of 10 months . A similar rate of relapse was noted in a retrospective study of 29 patients who received mycophenolate mofetil for maintenance therapy (48 percent at a mean of 14 months) .
Another large trial, the Wegener Granulomatosis Etanercept Trial (WGET), compared etanercept with placebo as add-on therapy in patients who were receiving cyclophosphamide or methotrexate for maintenance . Etanercept provided no additional benefit and may increase the risk for malignancy; therefore, this drug should not be used for maintenance therapy.
Dosing of maintenance therapy
Dosing of rituximab — A variety of rituximab dosing strategies have been used, and it is not clear whether there is any one best option. Maintenance rituximab therapy is typically administered as 500 to 1000 mg every six months [55,63]. Some experts redose rituximab at four-month rather than six-month intervals . Others prefer an "on-demand" dosing strategy, in which peripheral B lymphocyte (CD19-positive cells) counts, which are depleted by rituximab, and ANCA titers are monitored and the drug is redosed when B lymphocytes reconstitute and the ANCA titer becomes positive. As an example, one study of 53 patients with GPA found that, after remission induction with rituximab, relapse only occurred in patients whose CD19-positive cell count increased above 20 cells/microL and whose PR3-ANCA titers were positive . By contrast, another study found that 29 percent of relapsing patients had depleted CD19-positive cell counts . A randomized trial comparing an individually tailored and fixed-schedule rituximab regimen (500 mg IV every six months) among 162 patients with newly diagnosed or relapsing GPA or MPA who achieved complete remission after induction therapy reported comparable rates of relapse over 28 months . The rates of adverse events and infectious complications were also similar between the two groups.
Some experts also routinely monitor serum immunoglobulin levels and reduce the dose of rituximab in patients who develop hypogammaglobulinemia. Others only monitor serum immunoglobulin levels if the patient develops frequent infections. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Hypogammaglobulinemia'.)
Rituximab should not be given to patients who are positive for HBsAg or anti-HBc, without concurrent HBV therapy, due to the elevated risk of reactivation and potentially fatal hepatitis. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
Dosing of azathioprine — Azathioprine is typically initiated at a dose of 50 mg/day and gradually increased if thiopurine methyltransferase (TPMT) testing has not been performed prior to initiation of therapy. If this dose is tolerated well at one week, the daily dose can be increased over several weeks to 2 mg/kg per day. If TPMT testing is performed prior to the initiation of therapy and is normal, azathioprine can be initiated at 2 mg/kg per day. The maximum dose should typically not exceed 200 mg/day. In some trials, the dose of azathioprine was reduced at one year to 1.5 mg/kg per day, but this corresponded to an increase in relapse rate [18,67]. Thus, we do not reduce the dose of azathioprine.
Azathioprine metabolism and toxicity is predominantly related to TPMT activity, which varies among individuals. However, there is uncertainty regarding the benefits of routine testing for TPMT deficiency before beginning azathioprine. Although some clinicians routinely perform TPMT testing prior to initiating azathioprine, others do not perform such testing but rather initiate therapy at a low dose with close monitoring as the dose is gradually increased. The use of TPMT testing along with other potential adverse effects are discussed in detail separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects'.)
Dosing of methotrexate — Methotrexate is typically initiated at a dose of 15 mg/week, with increases in dose every two to eight weeks of 5 mg/week up to 25 mg/week. We use the same regimen and approach to titration as that used in rheumatoid arthritis (see "Use of methotrexate in the treatment of rheumatoid arthritis"). This dosing strategy is similar to that used in the WEGENT trial and other studies [54,68]. Although methotrexate can be given both orally and subcutaneously, the bioavailability at such doses is superior through the subcutaneous route.
Because 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 per day), or folinic acid (5 to 10 mg per week, 24 hours after methotrexate) should be given concurrently to reduce potential toxicity.
Given the risk of methotrexate toxicity in patients with reduced kidney function, this drug should not be used in patients with an eGFR <60 mL/min/1.73 m2 or evidence of active renal vasculitis.
Dosing of mycophenolate — The target dose of mycophenolate mofetil is typically between 1.5 and 3 g daily, in divided doses. One option is the regimen from the IMPROVE study (starting at 2000 mg per day followed by a reduction to 1500 and 1000 mg per day after 12 and 18 months, respectively), although this dose reduction was associated with an increased rate of relapses when compared with azathioprine in one trial . Additional formulations (eg, enteric-coated mycophenolate sodium), dosing, and monitoring considerations for mycophenolate can be found elsewhere. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)
Duration of maintenance therapy — Our approach to the duration of maintenance therapy is based upon available data and clinical experience; other authorities have a different opinion about when to stop maintenance therapy. In addition, the duration of maintenance therapy should be modified if toxicity occurs:
●In most patients, we continue maintenance therapy for 12 to 24 months after stable remission has been induced [17,18,54,69].
●In patients with multiple risk factors for relapse (eg, PR3-ANCA seropositivity, pulmonary involvement, and upper respiratory tract involvement), we continue maintenance therapy for 24 to 36 months. Some experts would treat such patients indefinitely if the degree of organ damage was severe and a relapse would be poorly tolerated.
●We continue maintenance therapy indefinitely in patients who have had one or more prior relapses, particularly in those who sustained significant organ damage (eg, those with limited residual kidney function) and therefore would not tolerate further injury due to relapse.
●In some patients who have a low risk of relapse (eg, MPO-ANCA seropositivity and no respiratory tract involvement prior to remission), we continue maintenance therapy for 6 to 12 months. However, in such patients who become MPO-ANCA negative at the end of induction therapy, some experts would provide careful monitoring without any maintenance therapy.
Only two randomized trials have compared different durations of maintenance therapy:
●One trial compared standard duration (two years) and extended duration (four years) azathioprine maintenance therapy in 131 patients with newly diagnosed PR3-ANCA-associated vasculitis who received oral cyclophosphamide and glucocorticoids for induction therapy . At four years after diagnosis, rates of relapse-free survival were comparable between the two groups.
●The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN)3 trial evaluated the efficacy of an extended rituximab maintenance regimen (500 mg given every 6 months over an additional 18 months) among 97 patients who had achieved complete remission after induction therapy and completing an initial 18-month rituximab maintenance regimen . After 28 months of follow-up, the extended rituximab maintenance group had a lower incidence of relapse compared with the placebo group (4 versus 26 percent, respectively). In the placebo group, relapses were more common among patients who were PR3-ANCA positive than among those who were MPO-ANCA positive (40 versus 12 percent, respectively). Only one patient out of 29 with persistently negative ANCA levels relapsed, and none of five patients with both negative ANCA levels and undetectable CD19+ B cells relapsed. No deaths occurred in either group, and the frequency of adverse events was similar in both groups.
In addition, patients at lower risk for relapse (eg, MPO-ANCA-positive disease) may remain in remission without maintenance therapy after induction of remission. Some observational studies have found that discontinuation of maintenance therapy has not been associated with a substantial increase in relapses [71,72]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Risk factors for relapse'.)
Patients who progress to ESKD and are treated with chronic dialysis have a substantially lower rate of relapse than the same patients before they reached ESKD or patients with preserved kidney function. The management of patients with GPA or MPA who have ESKD is presented elsewhere. (See 'Maintenance dialysis' below.)
The use of ANCA titers to predict relapse is presented elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Monitoring for relapse'.)
Non-organ- and non-life-threatening disease — Patients with non-organ- and non-life-threatening GPA include those with rhinosinusitis, arthritis, and/or pulmonary nodules with no other major organ involvement [73-78]. (See 'Assessment of disease severity' above.)
For patients with non-organ- and non-life-threatening GPA not involving the kidney, we suggest induction therapy with glucocorticoids combined with weekly oral methotrexate (20 to 25 mg per week orally), rather than glucocorticoids combined with cyclophosphamide, rituximab, or azathioprine. However, given the risk of toxicity in patients with kidney dysfunction, methotrexate should not be used when the eGFR is below 60 mL/min per 1.73 m2 or if there is evidence of active glomerulonephritis. Rituximab is a reasonable alternative as induction therapy, even in non-organ- and non-life-threatening disease. Azathioprine may be used as an alternative to methotrexate for pregnant patients or patients for whom methotrexate should be avoided due to moderate to severe kidney function impairment. However, there are no high-quality data regarding use of azathioprine for induction of remission in this patient population, and, in our experience, azathioprine may take longer than methotrexate to become maximally effective as an immunosuppressive agent. If rituximab is used, we use the same dose as that used for induction therapy in patients with organ- or life-threatening disease. If azathioprine is used, we use the same dose as that used for maintenance therapy in patients with organ- or life-threatening disease. (See 'Rituximab-based regimen' above and 'Dosing of azathioprine' above.)
Methotrexate may be continued as maintenance therapy at the same dose used for induction, provided that patients have responded to induction therapy. Similarly, if rituximab or azathioprine is used as induction therapy, it may also be continued as maintenance therapy. Maintenance dosing for rituximab and azathioprine is similar to that for patients with organ- or life-threatening disease and is discussed above. (See 'Dosing of rituximab' above and 'Dosing of azathioprine' above.)
Patients with non-organ- and non-life-threatening disease may be able to be treated with lower doses of glucocorticoids than used for patients with organ- or life-threatening disease. We typically initiate prednisone at 0.5 mg/kg/day (or its equivalent) followed by a reduced-dose glucocorticoid taper. Details about glucocorticoid dosing and taper are presented elsewhere in this topic. (See 'Glucocorticoid dosing and taper' above.)
Available data suggest that methotrexate is as effective for induction of remission in patients with non-organ- and non-life-threatening disease but may be associated with a higher relapse rate. The Nonrenal Wegener's Granulomatosis Treated Alternatively with Methotrexate (NORAM) trial compared methotrexate and cyclophosphamide for both induction and remission in 89 patients with newly diagnosed GPA and six patients with MPA, none of whom had significant kidney 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 . 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). 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 the WGET trial; remission rates with methotrexate were similarly high in this subset of patients with GPA .
Monitoring the response to therapy — All patients receiving immunosuppressive therapy for GPA or MPA should be closely monitored.
Patients with organ- or life-threatening disease are typically admitted to the hospital for treatment with close monitoring of their clinical status and laboratory testing on a daily basis. If the patient has pulmonary hemorrhage, serial chest radiographs and/or a computed tomography (CT) of the chest are reasonable to monitor for worsening alveolar hemorrhage. When the patient's condition is stable enough for discharge from the hospital, we typically schedule follow-up visits every two to four weeks for the first three months. Subsequently, the duration between follow-up visits can then be extended to every two to three months. The goal of these visits is to evaluate the patient's response to therapy (ie, whether a clinical response is achieved) and the toxicity of the regimen (ie, adverse effects, infections due to immunosuppression). We perform the following assessments during these visits:
●History and physical examination
●Assessment of blood pressure
●Measurement of serum creatinine and electrolytes
●Urinalysis with microscopic examination of the urinary sediment
●Complete blood count
●Erythrocyte sedimentation rate and/or C-reactive protein level
Clinical practice varies in the monitoring of ANCA titers among patients being treated for GPA or MPA. Some authors and editors routinely monitor ANCA titers, particularly among patients with kidney involvement, to assess the response to therapy and risk of relapse [65,79-82]. Other contributors do not routinely monitor ANCA titers, since ANCA titers do not consistently reflect disease activity. Additional information about ANCA titers in patients with GPA or MPA is presented elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Monitoring by the clinician'.)
Additional organ-specific testing may be required for some patients. As an example, repeat CT of the chest is advised for patients with tracheal and/or pulmonary involvement to document remission or prior active disease and/or to establish a new baseline. In addition, serial audiograms should be performed in patients with any form of hearing loss related to GPA or MPA.
Other treatment considerations
Treatment-associated toxicity — Cyclophosphamide, rituximab, azathioprine, methotrexate, mycophenolate, and glucocorticoids are all associated with important toxicity. In addition to the toxicities discussed below, cytotoxic agents are toxic to the fetus. (See "Pregnancy in patients with nondialysis chronic kidney disease" and "Safety of rheumatic disease medication use 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:
●Rituximab (see "Rituximab: Principles of use and adverse effects in 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")
Prevention of opportunistic infections and vaccinations — We typically administer prophylaxis to prevent Pneumocystis jirovecii pneumonia in all patients initiating immunosuppressive therapy with cyclophosphamide or rituximab in combination with prednisone at a dose ≥20 mg/day (or equivalent dose of a different glucocorticoid). We discontinue prophylaxis when the dose of prednisone is tapered to less than 5 to 10 mg/day. Most commonly, we use trimethoprim-sulfamethoxazole (one single-strength [80 mg/400 mg] tablet daily or one double-strength [160 mg/800 mg] tablet three times per week). Other prophylactic regimens are discussed in detail separately (see "Treatment and prevention of Pneumocystis pneumonia in patients without HIV"). In one patient cohort, Pneumocystis pneumonia developed in 11 of 180 patients (6 percent) with GPA, all of whom were treated with daily glucocorticoids and a second immunosuppressive drug .
In addition to P. jirovecii pneumonia, patients treated with immunosuppressive therapy for GPA or MPA are at high risk for infections [84,85]. Given this increased risk of infection, patients should receive age-appropriate vaccinations, including those against pneumococcus, influenza, and herpes zoster (see "Immunizations in autoimmune inflammatory rheumatic disease in adults"). In one large study, for example, the cumulative incidence of infection was 51 percent during the first year of treatment . Most infections involved the respiratory tract, and most positive cultures revealed Staphylococcus aureus.
Management of respiratory tract and upper airway involvement — The management of central airway obstruction and diffuse alveolar hemorrhage are discussed separately. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults" and "The diffuse alveolar hemorrhage syndromes", section on 'Treatment'.)
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 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 [86,87].
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 . (See "Clinical presentation, diagnostic evaluation, and management of malignant 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 . Grafts prepared from a patient's costal or auricular cartilage, iliac or other bone, or dura have been used with varying success.
Pregnant patients — There is only limited information on pregnancy complicated by granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) [90,91]. The major challenges in treating active disease during pregnancy are the moderate to high risk of fetal harm associated with various therapies used for induction or maintenance of remission, including cyclophosphamide, methotrexate, and mycophenolate. In addition, there are limited data regarding the safety of rituximab in pregnancy:
The immunosuppressive drugs considered safer during pregnancy 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 rituximab or cyclophosphamide in the second or third trimester once organogenesis is complete, although data are limited and the risks and benefits must be weighed carefully.
The ongoing online 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.
Older patients — Among patients with GPA or MPA, it is not uncommon for patients to present with new-onset disease at age 75 years or older. Studies have demonstrated that older age is an independent risk factor for worse outcomes in ANCA-associated vasculitis, both due to life-threatening infections and to disease-related morbidity, notably end-stage kidney disease (ESKD) [92,93]. The increased risk of serious infections in older patients and the substantive risk of infection associated with glucocorticoids highlight the need to use "glucocorticoid-sparing" approaches in this patient population.
Older patients with ANCA-associated vasculitis respond well to the same treatment approaches to induction of remission as do younger patients , and use of rituximab or cyclophosphamide (in reduced dosing based on kidney function and age) should not be withheld due to age. Regimens to maintain remission in ANCA-associated vasculitis are especially important for older patients to avoid repeat use of glucocorticoids and to preserve residual kidney function. However, as with all treatment of ANCA-associated vasculitis, the risks of prolonged immunosuppression and infection must be weighed against the benefits of avoiding a relapse of vasculitis.
Patients with end-stage kidney disease
Maintenance dialysis — Little is known concerning the optimal treatment of patients with GPA or MPA who develop ESKD and require maintenance dialysis. Such patients have a higher risk of death as compared with patients who do not develop ESKD. (See 'Prognosis and other outcomes' below.)
Further management varies with the clinical setting:
●No active disease – If the patient has no evidence of active kidney disease (ie, absence of hematuria with dysmorphic red cells in the urine sediment, which must be distinguished from isomorphic [normomorphic] hematuria that may be due to cyclophosphamide-induced bladder injury) and has no active extrarenal disease, we continue immunosuppressive therapy until the patient has completed three to six months of maintenance therapy. If, at that time, the patient continues to have inactive disease, then we typically discontinue immunosuppressive therapy. (See 'Maintenance therapy' above.)
It is unclear how much benefit is provided by usual maintenance therapy to prevent relapse in patients with ESKD since the rate of relapse is substantially reduced in dialysis [94,95]. In an analysis of 229 patients on maintenance dialysis followed for a mean of 4.6 years, the relapse rate decreased from 57 to 7 episodes per 100 person-years before and after dialysis initiation . During the follow-up period, 45 percent of patients had a serious infection and 45 percent had a cardiovascular event, while 13 percent experienced disease relapse.
●Active kidney but not extrarenal disease – If the patient has persistent dysmorphic hematuria and no extrarenal disease, we treat with immunosuppressive therapy in a manner similar to patients without ESKD with appropriate dose adjustments in medications for the kidney failure. The purpose of continued therapy in patients with active kidney but without extrarenal manifestations is that control of the renal vasculitis might result in enough recovery of kidney function to permit the discontinuation of dialysis. However, treating such patients beyond four months is of limited benefit . (See 'Induction therapy' above and 'Maintenance therapy' above.)
●Active extrarenal disease – We and other investigators treat patients on chronic dialysis with active extrarenal GPA or MPA in the same manner as those who do not require maintenance dialysis, with the duration of therapy and therapeutic regimen being based upon patient response and whether relapse has occurred and with appropriate dose adjustments in medications for the kidney failure. (See 'Induction therapy' above and 'Maintenance therapy' above.)
Even if a decision is made to discontinue immunosuppressive therapy in patients on chronic dialysis, it is imperative that all patients with a history of GPA or MPA be followed indefinitely for the potential to relapse in other organ systems, even many years following the onset of kidney failure.
The following immunosuppressive drugs should either not be used or not be used at standard doses in patients with ESKD:
●Methotrexate should not be given as maintenance therapy to patients who are on dialysis or have moderate to severe chronic kidney disease.
●Given the increased risk of severe bone marrow suppression in patients with ESKD, cyclophosphamide should be used cautiously with careful monitoring. Dose adjustment for cyclophosphamide in dialysis patients is not well defined. A suggested approach for oral cyclophosphamide is 50 percent of the usual dose after each hemodialysis session and 75 percent of the usual dose in patients on continuous ambulatory peritoneal dialysis (table 1).
Kidney transplantation — Patients who develop ESKD due to GPA or MPA are potential candidates for kidney transplantation. At a minimum, transplantation should be delayed for at least six months from the time of initial presentation or most recent relapse . The presence of a positive ANCA titer at the time of transplantation does not appear to predict recurrence of glomerulonephritis in the transplanted organ. Thus, persistence of an isolated positive ANCA titer is not a contraindication to kidney transplantation.
It is likely that the immunosuppression administered for the prevention of allograft rejection contributes to the prevention of disease flares among patients with GPA or MPA [98,99].
Several studies have shown that long-term outcomes of patients with GPA or MPA who receive a kidney transplant are comparable to those of patients transplanted for other causes of ESKD [100-103].
Drug-induced ANCA-associated vasculitis — Certain medications (eg, hydralazine, propylthiouracil, minocycline) may induce vasculitis associated with antineutrophil cytoplasmic autoantibody (ANCA), mostly myeloperoxidase (MPO)-ANCA. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis'.)
The optimal management of drug-associated ANCA and the course of the disease are uncertain given the limited reports in the literature. Discontinuation of the offending agent may be the only intervention necessary for mild cases of ANCA-associated vasculitis induced by medications. Examples include cases presenting with constitutional symptoms, arthralgias/arthritis, or cutaneous vasculitis, but without lung or kidney involvement.
Patients with more severe disease manifestations such as lung or kidney involvement, which are common with hydralazine, require treatment with high doses of glucocorticoids and even rituximab or cyclophosphamide. As an example, in one series of 80 cases of hydralazine-induced ANCA-associated glomerulonephritis, 42 of 51 patients with long-term follow-up received immunosuppressive therapy . (See 'Induction therapy' above and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Hydralazine'.)
Patients with drug-induced ANCA-associated vasculitis do not typically require maintenance therapy; relapse should not occur if the responsible drug is discontinued. However, attributing ANCA-associated vasculitis to a drug may be incorrect, and therefore careful and frequent monitoring of the patient is required after discontinuation of the presumed causative agent.
The risk of recurrence with re-exposure to the drug is unclear. Given the potential morbidity associated with drug-induced ANCA-associated vasculitis, we do not advocate for rechallenge with the potentially offending agent.
Double-positive ANCA and anti-GBM disease — Patients who are double positive for antineutrophil cytoplasmic autoantibody (ANCA) and anti-glomerular basement membrane (anti-GBM) antibodies should be managed initially as patients with anti-GBM disease since this is the more severe lesion. The initial treatment of such patients should include plasmapheresis plus immunosuppressive therapy, even among those with dialysis-requiring kidney failure. These issues are discussed in more detail elsewhere. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis", section on 'Double-positive anti-GBM and ANCA-associated disease'.)
However, unlike patients with single-positive anti-GBM disease, double-positive patients will require maintenance therapy for ANCA disease because of the tendency of vasculitis to relapse. (See 'Maintenance therapy' above.)
INVESTIGATIONAL APPROACHES — Several investigational agents have been tried or are under investigation for patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), including abatacept , belimumab , vilobelimab, and B cell-targeted immunotherapy . Additional studies are required before these therapies can be routinely used in clinical practice.
PROGNOSIS AND OTHER OUTCOMES — Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are associated with considerable morbidity and mortality that are due to either irreversible organ dysfunction from inflammatory injury or the consequences of prolonged and/or intensive therapy with glucocorticoids and other immunosuppressive agents:
●Mortality – Untreated patients have a 90 percent mortality rate within two years. The long-term survival in patients with GPA and MPA has improved dramatically since the additions of cyclophosphamide and rituximab to the therapeutic regimen [108,109]. However, patients with GPA and MPA still have a higher mortality rate compared with the general population [110,111]. A meta-analysis of observational studies of patients with GPA and MPA reported a 2.7-fold increased risk of death in patients compared with the general population (95% CI 2.26-3.24) .
The major causes of death in patients with GPA and MPA are complications from immunosuppressive therapy (primarily infection), complications from the underlying disease (eg, kidney failure, pulmonary failure), and cardiovascular disease [94,112-114].
Higher mortality rates are observed among older adults and those who present with florid organ failure, such as patients with diffuse pulmonary hemorrhage requiring ventilatory support or advanced kidney dysfunction [115,116]. End-stage kidney disease (ESKD) and overall mortality are higher in older adult patients (age >80 years). As an example, a retrospective study including 78 patients >80 years old who had biopsy-proven pauci-immune glomerulonephritis, of whom 93 percent had a positive ANCA, found that ESKD was more common in the untreated group at one year (73 versus 36 percent) .
●Malignancy risk – Some studies suggest that patients with GPA or MPA may have a higher incidence of cancer compared with the general population, with estimates ranging from 10 to 26 percent . The increased risk of malignancy has been described with non-melanoma skin carcinomas (NMSCs), hematologic malignancies, and bladder, breast, lung, prostate, and colorectal carcinomas [119,120]. To some degree, some of the increased risk is associated with immunosuppressive treatment . As treatment regimens for GPA and MPA have evolved over the past decade to include shorter courses of cyclophosphamide, more contemporary studies have suggested that the risk of cancer may be decreasing [119,122].
●Infection – Approximately 25 to 30 percent of patients with GPA and MPA will develop a serious infection that requires hospitalization, with respiratory infections being the most common [123-126]. Patients are at highest risk for infection in the first year after diagnosis, which is most likely related to the higher intensity of immunosuppression during this time period, including the use of high-dose glucocorticoids [123,127,128].
The use of immunosuppressive agents to treat GPA and MPA is a primary factor contributing to the risk of infection in these patients. Several studies have evaluated the risk of infection associated with different immunosuppressive regimens used to treat GPA or MPA. As an example, two randomized trials found no difference in infection rates between patients receiving a rituximab-based regimen and those receiving a cyclophosphamide-based regimen as induction therapy [19,21]. Trials comparing different maintenance regimens have reported similar rates of infection among patients treated with azathioprine, methotrexate, mycophenolate mofetil, rituximab, or oral cyclophosphamide [18,54-56].
●End-stage kidney disease – Since the kidney is a frequent target organ in patients with either GPA or MPA, progressive kidney failure may be observed. In different series with a variable duration of follow-up, ESKD occurred in 10 to 26 percent of patients [2,94,112,115,129-132]. The incidence of ESKD among patients with GPA and MPA has fallen over the past several decades. In a study of an inception cohort of 554 patients with kidney disease at time of diagnosis, the five-year risk of ESKD decreased over time . Serum creatinine at baseline was the only significant predictor of risk of ESKD.
The principal determinants of a poor kidney outcome include more severe kidney dysfunction at presentation, lack of response to initial treatment, renal relapses, age greater than 65 years, and prominent fibrotic changes, such as interstitial fibrosis and glomerulosclerosis on initial kidney biopsy [2,115,129,133-135]. By comparison, responsiveness to immunosuppressive therapy and improved kidney function over time can be observed among patients with predominantly active kidney lesions at disease presentation.
Severe initial kidney involvement does not preclude the induction of remission or clinically significant improvement in kidney function with appropriate therapy. In a report of newly diagnosed patients, remission was induced in 72 percent of 240 patients with an estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2, 68 percent of 188 patients with an eGFR ≤20 mL/min/1.73 m2, and 57 percent of 96 patients with an eGFR ≤10 mL/min/1.73 m2 . On the other hand, severe kidney disease at presentation was also a risk factor for cyclophosphamide resistance (odds ratio 1.28 per 1.13 mg/dL [100 micromol/L] elevation in serum creatinine).
Among patients who require dialysis during the acute phase of the disease, 55 to 90 percent recover enough function to come off dialysis [3,115,129,136-138], with 40 to 70 percent being maintained off dialysis for three years or more [3,139].
●Cardiovascular risk – Patients with GPA or MPA may have an increased risk of cardiovascular events, including thromboembolism [140-146]. In a cohort study that examined cardiovascular events among 2306 patients with GPA or MPA and 6918 controls, a diagnosis of GPA or MPA was associated with an increased risk of ischemic heart disease (HR 1.86, 95% CI 1.62-2.15), heart failure (HR 2.12, 95% CI 1.77-2.54), myocardial infarction (HR 1.62, 95% CI 1.26-2.09), atrial fibrillation (HR 2.08, 95% CI 1.82-2.39), ventricular arrhythmia/defibrillator implantation (HR 2.04, 95% CI 1.16-3.57), and ischemic stroke (HR 1.58, 95% CI 1.31-1.90) . Patients with GPA or MPA also had an increased risk of undergoing percutaneous coronary intervention (HR 1.56, 95% CI 1.17-2.07) and in-hospital cardiac arrest (HR 2.27, 95% CI 1.49-3.48).
The reasons for an increased risk of cardiovascular disease among patients with GPA and MPA are not clear, but some investigators speculate this may relate to the impact of nontraditional risk factors, including chronic inflammation, use of glucocorticoids, and chronic kidney disease. As an example, in a retrospective multinational study of 2286 patients with ANCA-associated vasculitis, risk factors for myocardial infarction and stroke included pulmonary and kidney involvement (HR 1.5 and 3.0, respectively), older age, and history of smoking .
Clinicians and patients are advised to be vigilant about evaluating and treating established risks of cardiovascular disease, including hypertension, diabetes mellitus, hyperlipidemia, and obesity; these comorbidities may be more prevalent among patients with GPA and MPA.
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
●Goals of therapy – The goal of therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is to achieve a rapid, long-standing remission. Treatment consists of an initial induction phase aimed to put patients with active disease into remission, followed by a maintenance phase that is intended to extend remission and prevent relapse. (See 'Goals of therapy' above.)
●Approach to initial therapy – Immunosuppressive therapy is warranted in almost all patients with active GPA or MPA. Our approach to initial therapy depends largely upon the severity of disease and the organ systems involved (algorithm 1):
•Organ- or life-threatening features include, but are not limited to, active glomerulonephritis, pulmonary hemorrhage, cerebral vasculitis, progressive peripheral or cranial neuropathy, orbital pseudotumor, gastrointestinal bleeding due to vasculitis, or cardiac disease due to vasculitis (pericarditis, myocarditis).
•Patients with non-organ- or non-life-threatening disease have no evidence of "active glomerulonephritis" (ie, serum creatinine that is stable compared with baseline and no red cell casts or proteinuria) and no organ-threatening or life-threatening manifestations. (See 'Assessment of disease severity' above.)
●Organ- or life-threatening disease
-Rituximab- or cyclophosphamide-based regimen – For patients with GPA or MPA who have organ- or life-threatening disease, we recommend an induction regimen consisting of glucocorticoids in combination with either rituximab or cyclophosphamide, rather than glucocorticoid monotherapy (Grade 1B). Some authors/editors choose a rituximab-based regimen for the majority of patients, given its comparable efficacy and different side-effect profile compared with cyclophosphamide. Other authors/editors favor a cyclophosphamide-based regimen as initial therapy, particularly in patients presenting with more severe kidney disease and/or pulmonary hemorrhage. Some authorities treat with glucocorticoids in combination with both rituximab and cyclophosphamide. (See 'Induction therapy' above.)
-Glucocorticoid dosing – For most patients with GPA or MPA receiving glucocorticoids in combination with a glucocorticoid-sparing agent, we recommend a reduced-dose glucocorticoid tapering regimen rather than the standard-dosing taper (Grade 1B). Dosing of glucocorticoids is discussed above. (See 'Glucocorticoid dosing and taper' above.)
-Role of plasma exchange – The authors/editors of this topic do not fully agree on the role of plasma exchange among patients with GPA or MPA. All authors agree with the use of plasma exchange in most patients with GPA or MPA who are concomitantly positive for anti-glomerular basement membrane (anti-GBM) autoantibody. Other authors would also offer plasma exchange in patients who present with pulmonary hemorrhage and/or severe active kidney disease with kidney biopsy findings showing active inflammation without significant glomerulosclerosis. (See 'Role of plasma exchange' above.)
•Maintenance therapy – In most patients who achieve remission after induction immunosuppressive therapy, we suggest treatment with rituximab for maintenance of remission (Grade 2C). Azathioprine, methotrexate, and mycophenolate are reasonable alternatives and may be preferred based on other patient-specific factors. Maintenance therapy in patients with newly diagnosed GPA or MPA is usually given for 12 to 24 months after stable remission has been induced. (See 'When to start maintenance therapy' above and 'Choice of maintenance therapy' above and 'Dosing of maintenance therapy' above and 'Duration of maintenance therapy' above.)
●Non-organ- and non-life-threatening disease – Patients with non-organ- or non-life-threatening disease have no evidence of "active glomerulonephritis" (ie, serum creatinine that is stable compared with baseline and no red cell casts or proteinuria) and no organ-threatening or life-threatening manifestations. For patients with non-organ- and non-life-threatening GPA not involving the kidney, we suggest initial therapy with glucocorticoids combined with weekly oral methotrexate rather than glucocorticoids combined with cyclophosphamide, rituximab, or azathioprine (Grade 2C). Rituximab is a reasonable alternative as initial therapy, even in non-organ- and non-life-threatening disease. Azathioprine may be used as an alternative to methotrexate for pregnant patients or patients for whom methotrexate should be avoided due to moderate to severe kidney function impairment. (See 'Non-organ- and non-life-threatening disease' above.)
●Monitoring – All patients receiving immunosuppressive therapy for GPA or MPA should be closely monitored. Patients with organ- or life-threatening disease are typically admitted to the hospital for treatment with close monitoring of their clinical status and laboratory testing on a daily basis. When the patient's condition is stable enough for discharge from the hospital, we typically schedule follow-up visits every two to four weeks for the first three months. Subsequently, the duration between follow-up visits can then be extended to every two to three months. The goal of these visits is to evaluate the patient's response to therapy and the toxicity of the regimen. (See 'Monitoring the response to therapy' above.)
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