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 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. As examples: Given the risk of toxicity with use of methotrexate in patients with reduced kidney function, 2 this drug should not be used in patients with an eGFR <60 mL/min/1.73 m 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: https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 14/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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 [18]. 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 [54]. 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 [54]. 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) [55]. 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 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 15/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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. Rituximab also appears to be effective as maintenance therapy in older adults (age >75 years) with GPA or MPA [24]. 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 [56]. 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 [58]. 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) [59]. 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 [17]. 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 [47]. Others prefer an "on-demand" dosing strategy, in which peripheral B lymphocyte (CD19-positive cells) counts, which are depleted by rituximab, https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 16/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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 [64]. By contrast, another study found that 29 percent of relapsing patients had depleted CD19-positive cell counts [65]. 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 [66]. 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'.) https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 17/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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 2 not be used in patients with an eGFR <60 mL/min/1.73 m 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 [56]. 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 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 18/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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 [70]. 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 [69]. 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.) https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 19/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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, 2 methotrexate should not be used when the eGFR is below 60 mL/min per 1.73 m 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 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 20/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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 [76]. 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 [17]. 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 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 21/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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: Cyclophosphamide (see "General toxicity of cyclophosphamide in rheumatic diseases") 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') Azathioprine (see "Pharmacology and side effects of azathioprine when used in rheumatic diseases") Methotrexate (see "Major side effects of low-dose methotrexate") Mycophenolate (see "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases") Glucocorticoids (see "Major side effects of systemic glucocorticoids") https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 22/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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 [83]. 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 [84]. 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. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 23/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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 [88]. (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 [89]. Grafts prepared from a patient's costal or auricular cartilage, iliac or other bone, or dura have been used with varying success. SPECIAL POPULATIONS 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: