Great progress has been made in the last 2 decades in the treatment of antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. Once associated with a very high mortality rate, current induction therapy with the combination of corticosteroids and cyclophosphamide or rituximab results in remission rates around 80%. This phenomenal improvement shifted the attention from induction therapy to optimizing maintenance therapy and preventing relapses. This article focuses on the maintenance of remission after it is attained. Optimizing maintenance therapy is predicated on identifying patients at risk of relapse, minimizing the adverse effects of chronic immunosuppression, determining its optimal duration, and tailoring treatment to the individual patient’s needs. These considerations have influenced the design of recent clinical trials of maintenance therapy.
Risk Factors for Relapse
It is well recognized that the risk of relapse is not uniform for all patients with ANCA vasculitis. It would, therefore, be ideal to target maintenance therapy to patients at moderate or high risk of relapse while sparing those at low risk from the risks and costs of chronic immunosuppression. Several risk factors of relapse have been identified from cohort studies and clinical trials. These include:
- Proteinase 3 (PR3)-ANCA serotype, which is associated with greater risk of relapse on the basis of cohort studies as well as randomized controlled trials with rituximab or cyclophosphamide independently of treatment modality;
- lung involvement and upper respiratory tract (ENT) disease;
- the persistence of PR3-ANCA positivity at the end of induction treatment;
- the choice of induction therapy (compared with treatment with daily oral cyclophosphamide, treatment with pulse intravenous cyclophosphamide, mycophenolate mofetil, or methotrexate was associated with significantly more frequent relapses); and
- a history of prior relapse.
A retrospective cohort study of 147 rituximab-treated patients aimed at developing a predictive model of relapse on the basis of patient characteristics at the time of the last rituximab dose or 1 year later (1). The model was able to categorize patients between high- and low-risk groups, but it could not provide a prediction at the individual patient level. From the time of the last rituximab dose, the predictive factors retained in the model were men, age >60 years, ANCA positivity, relapsing disease, ENT involvement, prednisolone dose, and concomitant immunosuppressants. Twelve months after rituximab, the factors retained were ANCA positivity (hazard ratio [HR], 2.73; 95% confidence interval [95% CI], 1.56 to 4.80; P<0.001), relapsing disease, ENT involvement, serum creatinine, and prednisolone dose but not B cell repopulation. It is noteworthy that the median times to relapse were 29.4 versus 72.2 months from the last rituximab dose in the high- and low-risk groups, respectively, and 22 and 69.6 months, respectively, from 1 year after the last rituximab dose.
Choice of Maintenance Immunosuppression
Whereas a long course of cyclophosphamide was previously a standard approach to ANCA vasculitis maintenance, the 2003 randomized controlled trial of cyclophosphamide versus azathioprine for the maintenance of remission (CYCAZAREM) demonstrated that a switch to the less toxic azathioprine after remission resulted in similar patient outcomes, including relapses. Azathioprine was subsequently shown to be superior to mycophenolate mofetil in preventing relapse (HR, 1.69 with MMF; 95% CI, 1.06 to 2.7; P=0.03), without a difference in adverse events between these two therapies (2). In addition, the safety profile of azathioprine compared favorably with that of methotrexate while maintaining similar efficacy at preventing relapses (3). Finally, in a randomized controlled trial, the addition of belimumab to maintenance treatment with azathioprine and corticosteroids did not reduce the risk of vasculitis relapses (HR, 0.88; 95% CI, 0.29 to 2.65; P=0.82) (4).
Several randomized controlled trials have evaluated the use of rituximab as maintenance therapy. The MAINRITSAN trial randomized 115 patients to rituximab therapy (500 mg ×2 followed by every 6 months ×3) or azathioprine (2 mg/kg per day ×2 years) following induction with cyclophosphamide (5). The relapse rate was higher in the azathioprine group than in the rituximab group (29% versus 5%, respectively; HR, 6.61; 95% CI, 1.56 to 27.96; P=0.002), with similar adverse event rates between groups. A follow-up study compared a fixed schedule (500 mg every 6 months) with a tailored approach with rituximab dosing at the time of B cell or ANCA reappearance or rising titer (6). Patients in the tailored dosing group received fewer doses over 18 months (median, three doses; interquartile range, two to four doses) than patients in the fixed dose group (five doses). The tailored rituximab dosing resulted in a 17% relapse rate compared with 10% relapse with fixed dosing (P=0.22), and the relapse-free survival was similar in the two groups (84% versus 86%; P=0.58). The RITAZAREM trial also compared maintenance therapy with rituximab versus azathioprine, but it differed from the MAINRITSAN trial by targeting exclusively patients with relapsing disease, using rituximab for (re-)induction, and using larger and more frequent doses of rituximab (1000 mg intravenously every 4 months ×5 doses). Preliminary results, reported in abstract form, suggest a significantly lower relapse rate with rituximab compared with azathioprine (HR estimate, 0.36; 95% CI, 0.23 to 0.57; P<0.001) but no significant differences in adverse events between the two groups.
Treatment with rituximab is associated with hypogammaglobulinemia, which may be severe (<300 mg/L) in <10% of patients. The risk of moderate or severe hypogammaglobulinemia (<500 mg/dl) does not appear to be associated with the cumulative dose of rituximab, but rather with women, prior exposure to cyclophosphamide, and prolonged use of prednisone (7). In a retrospective study of patients with ANCA vasculitis, treatment with rituximab alone was not associated with a higher standardized incidence ratio of malignancy compared with the general population. In contrast, the standardized incidence ratio among patients treated with cyclophosphamide and azathioprine was 3.2 (95% CI, 2.05 to 4.76; P<0.001) (8).
Duration of Maintenance Therapy
Determining the optimal duration of maintenance therapy has spurred clinical trials using azathioprine or rituximab as the immunosuppressive agent. In the AZA-ANCA trial, 45 patients who remained PR3-ANCA positive after induction therapy with cyclophosphamide and prednisolone were randomized to 2 versus 4 years of therapy with azathioprine (9). Although the relapse-free survival was greater in the prolonged treatment group (72% versus 51%), this difference did not reach statistical significance (relative risk, 0.65; 95% CI, 0.24 to 1.75; P=0.40) due to the early termination of the study with only half the target number of patients. The larger REMAIN trial enrolled 117 patients regardless of ANCA serotype or positivity. In this study, relapses were more frequent in the 2-year than the 4-year azathioprine treatment group (odds ratio, 5.96; 95% CI, 2.58 to 13.77; P<0.001); however, the longer treatment was associated with higher frequencies of cytopenia (P=0.07) and cardiovascular events (P=0.06) (10). The relapse rates were not statistically different between patients with PR3-ANCA and patients with myeloperoxidase (MPO)-ANCA (49% versus 35%, respectively; P=0.13); however, ANCA positivity at randomization was associated with relapse risk (51% versus 29%, respectively; P=0.02; odds ratio, 2.57; 95% CI, 1.16 to 5.68).
The duration of maintenance therapy with rituximab was evaluated in a randomized controlled trial in which 97 patients who were in remission after completing the MAINRITSAN 2 trial (6) were rerandomized to four more doses of rituximab (500 mg) versus placebo every 6 months (11). Relapse-free survival at 28 months was significantly greater in the rituximab compared with the placebo group (96% versus 74%; HR, 7.5; 95% CI, 1.67 to 33.7; P=0.008). Relapses occurred more frequently among patients who had a return of ANCA positivity (50% versus 15%). No patient with persistent B cell depletion who was ANCA negative had a relapse. Adverse events were similar in the two treatment groups.
In summary, controlled trials and cohort studies provide guidance as to the preferred regimen for maintenance therapy in ANCA vasculitis. The choice of maintenance therapy should be individualized on the basis of an assessment of the risk of relapse, the effect that a relapse would have (e.g., because of poor pulmonary or kidney “reserve”), the risks and costs of immunosuppression, and the patient’s preference.
- ( Patients at high risk of relapse can be recognized on the basis of the presence of risk factors, notably patients with PR3-ANCA and those who remain PR3-ANCA positive at the end of induction therapy.
- ( Maintenance therapy with rituximab has been demonstrated to be well tolerated and superior to azathioprine in preventing relapses in two large trials. The choice of the fixed dose versus tailored dosing depends in part on access to B cell and ANCA monitoring. For tailored dosing, we suggest B cell and ANCA testing every 3 months and redosing rituximab when B cell repopulation is detected, when the ANCA test turns positive again (from negative), or when there are substantial increases in titer.
- ( For patients who do not have access to or are allergic to rituximab, maintenance treatment with azathioprine remains the preferred choice.
- ( For patients at high risk of relapse, a longer (4-year) duration of maintenance therapy seems to be associated with improved relapse-free survival. It is, however, unclear whether this translates to improved organ or patient survival.
- ( There are few data to guide maintenance therapy in patients at low risk of relapse. It is conjectured that many of those can be followed expectantly without maintenance immunosuppression.
P.H. Nachman reports consultancy agreements with Chemocentryx (ad hoc), Chinook (ad hoc), and Hansa Biopharma (ad hoc); receiving research funding as site principal investigator for clinical trials from (current) Goldfinch-Bio, the National Institutes of Health (NIH), and Omeros as well as (past) Aurinia, ChemoCentryx, the Food and Drug Administration (FDA), and InflaRx; receiving honoraria from the American Society of Nephrology, FDA, and NIH; and serving as a scientific advisor or member of the Kidney Health Initiative (past) and the National Kidney Foundation Minnesota Chapter (past). The remaining author has nothing to disclose.
The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. Responsibility for the information and views expressed herein lies entirely with the author(s).
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