7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy : Peter A Merkel, MD, MPH, Andre A Kaplan, MD, Ronald J Falk, MD : Gerald B Appel, MD, Fernando C Fervenza, MD, PhD : Albert Q Lam, MD, Philip Seo, MD, MHS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 26, 2023. 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: (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".) (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of disease resistant to initial therapy".) https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 1/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease".) GENERAL PRINCIPLES 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 [6]. 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 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 2/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate inflammation or irreversible glomerular injury and thus, as an isolated finding, is not necessarily indicative of active disease [7]. 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) [8]. 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 [9] and Kidney Disease: Improving Global Outcomes (KDIGO) [10]. 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. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 3/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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): Active glomerulonephritis Pulmonary hemorrhage Cerebral vasculitis Progressive peripheral or cranial neuropathy Orbital pseudotumor Scleritis 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 [11]. 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 [12]. 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) [12]. 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. The role of plasma exchange in induction therapy is discussed below. (See 'Role of plasma exchange' below and 'Double-positive ANCA and anti-GBM disease' below.) https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 4/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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 2 (375 mg/m 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 [19]. 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 [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, 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 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 5/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 2 reduction to 5 mg per day by the end of six months) plus either rituximab (375 mg/m 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, 2 of which 62 had an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m , rates of remission were similar between the treatment groups [23]. 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 [24]. 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 [25], 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. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 6/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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 2 another 1 g dose) or the dosing regimen that was used in the RAVE trial (375 mg/m per week for four weeks) can be used. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Initial dose'.) Patients receiving rituximab should also receive glucocorticoids. The glucocorticoid regimen is discussed below. (See 'Glucocorticoid dosing and taper' below.) 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 [26]. 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) [15], 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 [15]. 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 2 2 mL/min/1.73 m . Other experts treat with 0.5 g/m every two weeks for three to six months. If the white blood cell and absolute neutrophil count at two weeks are above 2 3500/microL and 1500/microL respectively, we increase the next dose to 0.75 g/m and, after repeating these labs two weeks later, reevaluate the need for a dose reduction back 2 to 0.5 g/m . 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'.) https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 7/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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. Patients receiving oral or IV cyclophosphamide should also receive glucocorticoids. The regimen is discussed below. (See 'Glucocorticoid dosing and taper' below.) 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) [15]. 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 [30]. 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 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 8/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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 [31]. 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) [33]. 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'.) https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 9/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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 [34], 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 2 (defined by an eGFR <50 mL/min/1.73 m 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 [31]. 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 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 10/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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) [39]. 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 2 mL/min/1.73 m ), 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 [40]. 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 [31]. 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 [44]. 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 [44]. 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 [11] and KDIGO [12]. Alternative regimens 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- https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 11/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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 [48]. 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 [53]. 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 [52]. 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 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 12/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 13/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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