Tab Application Banner
  • Users Online: 1542
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2019  |  Volume : 14  |  Issue : 3  |  Page : 218-228

Recent advances in the management of antineutrophil cytoplasmic antibody-associated vasculitis

1 Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Internal Medicine, Clinical Immunology and Rheumatology Services, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication30-Oct-2019

Correspondence Address:
Dr. Aman Sharma
Department of Internal Medicine, Clinical Immunology and Rheumatology Services, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_141_19

Rights and Permissions

The prognosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has remarkably improved from an almost uniformly fatal disease about three decades back, to a chronic manageable disease with survival rates in excess of 80%. Induction of remission largely relies on cyclophosphamide or rituximab-based regimens, although emerging data suggest some potential role of mycophenolate mofetil (MMF), especially in milder disease phenotypes. Recent emphasis has shifted to exploration of treatment regimens minimizing dosage and duration of corticosteroid exposure, or replacing corticosteroids altogether with agents like avacopan, in an effort to ameliorate risks due to glucocorticoids as well as minimize damage accrual. Maintenance regimens traditionally have used azathioprine, methotrexate, or less commonly, MMF. However, rituximab is emerging as a useful maintenance agent, with the advantage of single-dose administration 6 monthly. Dosing interval for rituximab maintenance is another area of active research, with emerging literature suggesting the effectiveness of a dosing schedule based on B-cell repopulation or rise in ANCA titers. Long-term considerations for patients with AAV include the risk of infections (which can be minimized with alternate-day cotrimoxazole therapy), hypogammaglobulinemia in patients on rituximab, and accrual of damage, including drug-related damage (such as diabetes and osteoporosis) and malignancies. Ongoing clinical trials attempt to decipher the role of plasma exchange, as well as delineate the exact role of newer steroid-sparing therapeutic modalities such as avacopan. Recent clinical guidelines for the management of AAV from multiple societies, including the European League against Rheumatism and the British Society for Rheumatology, provide common treatment recommendations for AAV management.

Keywords: Antineutrophil cytoplasmic antibody, eosinophilic granulomatosis with polyangiitis, granulomatosis with polyangiitis, microscopic polyangiitis, remission induction, remission maintenance

How to cite this article:
Misra DP, K Naidu G S, Sharma A. Recent advances in the management of antineutrophil cytoplasmic antibody-associated vasculitis. Indian J Rheumatol 2019;14:218-28

How to cite this URL:
Misra DP, K Naidu G S, Sharma A. Recent advances in the management of antineutrophil cytoplasmic antibody-associated vasculitis. Indian J Rheumatol [serial online] 2019 [cited 2020 May 29];14:218-28. Available from:

  Introduction Top

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a multisystem small-vessel vasculitis, with the spectrum of clinical manifestations ranging from localized disease, like sinusitis or orbital granulomas, to devastating, multisystem illness involving the lungs, kidneys, and nervous system. Three major phenotypes are recognized, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA).[1] A majority of patients with GPA are positive for antiproteinase 3 (anti-PR3) ANCA, whereas most patients with MPA are positive for antimyeloperoxidase (anti-MPO) ANCA. From an illness associated with nearly 90% fatality at 2 years, advances in therapeutics in the past two decades have transformed long-term survival rates to >80% at 2 years.[2] Therapeutic advances in this field continue at a remarkable speed. In this narrative review, we shall review recent advances related to the management of AAV.

  Search Strategy Top

Using previously published guidelines for writing narrative reviews,[3] we searched PubMed (including MEDLINE and PubMed Central) on August 29, 2019, using the search term “ANCA vasculitis” and retrieved 6569 results. Limiting our search to articles published from January 1, 2015 onward resulted in 1744 articles, whose titles and abstracts were manually screened to identify clinical trials and case series reporting management of AAV. Additional older articles of critical importance were included based on the authors' personal knowledge.

  Remission Induction in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Top

The prognosis of AAV has been dramatically altered since the 1980s, when cyclophosphamide-based regimens came into vogue. Initially, the treatment of choice was daily oral cyclophosphamide, the scenario changed after the landmark CYCLOPS trial in the first decade of the 21st century, wherein 73 patients treated with daily oral cyclophosphamide (2 mg/kg/day) were compared to 76 patients treated with pulsed intravenous cyclophosphamide (15 mg/kg every 2–3 weeks) in a randomized controlled trial. Although remission rates by 9 months were similar, patients treated with intravenous cyclophosphamide had lower rates of leucopenia and lesser cumulative exposure to cyclophosphamide.[4] Long-term follow-up data from this trial were recently published. Although relapse rates were higher in the intravenous cyclophosphamide arm compared to the oral cyclophosphamide arm (hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.26–0.93), long-term survival, number of deaths, or patients progressing to end-stage renal disease (ESRD) were similar in both groups. The findings of this trial suggested the feasibility of using intravenous cyclophosphamide as an induction treatment for AAV.[5] A retrospective analysis of 57 AAV patients each treated with oral or intravenous cyclophosphamide from the United Kingdom (UK) reaffirmed the similar effectiveness of the two regimens, with respect to remission of active disease and subsequent relapses; risk of neutropenia was higher in patients on oral cyclophosphamide.[6] Intravenous pulse cyclophosphamide has also been the drug of choice in a study of 105 GPA patients from India.[7] The CORTAGE trial assessed whether a lower dose of intravenous cyclophosphamide may be feasible for remission induction in older patients (>65 years) with AAV. Fifty-one patients were treated with the standard intravenous cyclophosphamide regimen, and 53 were treated with a fixed-dose regimen of 500 mg intravenous cyclophosphamide 2–3 weekly for six doses. Serious adverse events, most of which were serious infections, were lesser in the lower dose regimen. Treatment failures were similar in both groups; although relapses were 15% more in the lower dose regimen, this did not attain statistical significance.[8] Two recent clinical trials have assessed mycophenolate mofetil (MMF) as an alternative agent to cyclophosphamide for induction of remission. A transatlantic multicentric study assessed remission induction in 43 patients on oral cyclophosphamide and 41 patients on MMF 2 g daily for 6 months each, with azathioprine used for maintenance of remission after 6 months. At 6 months, 81% patients on cyclophosphamide attained remission, compared to 66% on MMF. At 2 years, disease-free survival was 61% in the cyclophosphamide arm and 43% in the MMF arm; disease-free survival at 4 years was 39% versus 32%, respectively. Although none of these differences attained statistical significance, at all time points, numerically, more cyclophosphamide-treated patients had better outcomes.[9] In another multicentric clinical trial from Europe and Australia (the MYCYC trial), 140 AAV patients were randomized (70 each) to receive MMF (2–3 g/day) or intravenous pulsed cyclophosphamide (15 mg/kg every 2–3 weeks) until remission induction, followed by oral azathioprine at the time of remission induction in both groups for maintaining remission. Sixty-seven percent patients on MMF and 61% on cyclophosphamide attained remission at 6 months. Relapses were more in the MMF arm, especially those who were positive for anti-PR3 ANCA. Adverse effect profile was similar in both groups.[10] The findings of the MYCYC trial should be interpreted with caution in view of certain inconsistencies in the data highlighted in subsequent letters to the journal, as well as the lack of improvement of renal functions significantly in either arm, contrary to previous literature.[11] Overall, MMF may be an alternative agent for remission induction in milder AAV, positive for ANCA other than anti-PR3 antibodies.[9],[10],[11] Another important consideration while using intravenous cyclophosphamide is the need to modify (i.e., reduce) the dose of each intravenous cyclophosphamide pulse based on the estimated creatinine clearance.

Two landmark clinical trials published in 2010 evaluated the alternative induction regimen of rituximab in AAV. The Rituximab in ANCA vasculitis (RAVE) trial was conducted across multiple North American centers and compared a regimen of weekly rituximab 375 mg/m2 for 4 weeks with oral cyclophosphamide (2 mg/kg/day) for remission induction in 197 patients with GPA or MPA. The primary end point, proportion of patients attaining remission at 6 months, was similar in both groups (64% for rituximab and 53% for cyclophosphamide). In 101 patients with relapsing disease, 51 receiving rituximab and the rest cyclophosphamide, significantly greater proportions of patients attained remission with rituximab (67% vs. 42%). Recovery of renal function, remission in patients with diffuse alveolar hemorrhage, and adverse effect profile, were similar in both groups.[12] In a subgroup analysis of 102 patients with renal involvement (equal numbers randomized to rituximab or cyclophosphamide), proportions of patients attaining complete remission at 6 months (61% for rituximab and 63% for cyclophosphamide) and at 18 months (75% for rituximab and 76% for cyclophosphamide) were comparable, with similar proportions of relapses during this time period and similar adverse effect profile.[13] Patients enrolled in the RAVE trial who had relapses were more likely to be positive for anti-PR3 ANCA, have a clinical diagnosis of GPA, or have a relapsing disease.[14] A parallel study from European centers, the RITUXVAS trial, evaluated the role of a similar weekly rituximab regimen along with two 2-weekly pulses of intravenous cyclophosphamide (15 mg/kg, in 33 patients), to a standard regimen of intravenous cyclophosphamide pulses (in 11 patients), and reported similar remission rates at 1-year in both groups (76% for rituximab and 82% for cyclophosphamide). All these patients had renal involvement, and similar recovery of renal function was noted in both groups. Both these groups had similar rates of adverse events, including deaths.[15] In a long-term follow-up at 2 years of these patients, similar proportions of deaths, ESRD, or relapses were noted in both groups (42% for rituximab and 36% for cyclophosphamide).[16] Real-life data also suggest the efficacy of rituximab in inducing remission of active disease in >80% with active AAV, although response rates for granulomatous manifestations were as low as 30%.[17] However, case series have also demonstrated the utility of rituximab as an induction regimen in localized, ocular disease in up to 86% at 6 months[18] and in upper airway manifestations (odds ratio of 11 for period of inactive disease on rituximab, compared to active disease on rituximab).[19] Increasingly, biosimilars or biomimics of innovator biologic agents are being available to patients. A recent study presented data from India on the use of a rituximab biomimic in real-world settings. Fifty-six patients with GPA were treated with rituximab, in 45 of whom the indication for use was remission induction. At 6 months and 2 years, 71% and 86% patients, respectively, had attained remission. About 30% patients had developed infections by 2 years, similar to data from previous reports[15] on the use of rituximab. The results of this study suggest the feasibility and safety of rituximab biomimic as a therapeutic agent in AAV.[20]

The role of rituximab as a treatment option in EGPA is less clear and based on retrospective studies. A review of 41 patients with EGPA treated with rituximab revealed complete remission in 34% and 49% and partial remission in 49% and 39%, at 6 and 12 months, respectively.[21] Another retrospective study of 14 patients with EGPA reported complete or partial remission in all patients at 6 months.[22] Recent studies have evaluated different dosing regimens of rituximab in AAV. A retrospective analysis of 28 AAV patients from Japan (17 treated with standard rituximab dosing of 375 mg/m2 for 4 weeks and 11 treated with 2 weekly doses of rituximab 375 mg/m2) reported similar remission rates at 1-year (91% for low-dose and 88% for high-dose rituximab) as well as similar relapse rates during this period (20% for low-dose and 13% for high-dose rituximab), with similar levels of B-cell depletion in both groups.[23] Another pilot study of 17 patients with AAV from the UK evaluated the potential efficacy of a single dose of rituximab 375 mg/m2 to induce remission in AAV. Eighty percent patients attained remission at 3 months with this regimen, and potential savings in costs compared to a 4 week regimen of rituximab were >7000 United States (US) dollars.[24] It must be kept in mind that data regarding such low-dose rituximab regimens is sparse, and these require further exploration in prospective, randomized trials, before they can be recommended in clinical practice. Treatment options in patients who cannot tolerate rituximab due to hypersensitivity reactions include of atumumab, a monoclonal antibody to CD20, which helped attain remission in all eight treated patients along with low-dose cyclophosphamide in a retrospective case series from the UK.[25]

Two recent papers have reported the results of a combined regimen of rituximab and cyclophosphamide for remission induction in AAV from the real-life clinic settings. The CycLowVas study reported outcomes in 66 patients with AAV from the UK treated with 2 weekly doses of rituximab 1 g, along with intravenous cyclophosphamide 10 mg/kg (up to 750 mg) at 0 and 2 weeks, then four doses of 500 mg at 2 week intervals, along with corticosteroid in tapering doses. 94% of these patients attained complete remission at 6 months; all remained in remission at 1-year, 93% at 3 years, and 70% at 5 years. Nine patients died (median time to death 29 months), and four developed ESRD on follow-up. Outcomes were comparable with historical data from the European Vasculitis Society (EUVAS) trials.[26] Another report of 129 patients with AAV from the USA reported results with a regimen of oral cyclophosphamide (2.5 mg/kg/day for 1 week, followed by 1.5 mg/kg/day for 7 weeks), along with intravenous rituximab 1 g at 0 and 2 weeks, repeated every 4 months, with tapering doses of prednisolone. 84% patients attained complete remission of disease activity at 5 months follow-up. There were six relapses over 122 patient-years follow-up. Nine patients developed ESRD and two died.[27] These reports suggest favorable long-term outcomes with a combination of rituximab and cyclophosphamide for remission induction in AAV. Such a regimen may also be effective in those patients with refractory disease course with multiple relapses.[28]

Traditionally, corticosteroids have been considered the mainstay of treatment for AAV. Intravenous methylprednisolone pulses are generally used in patients with active AAV to induce remission. However, a recent paper retrospectively analyzed outcomes in 52 patients with AAV who received intravenous methylprednisolone pulses for active disease compared with 62 other patients from the same centers who did not receive this treatment. Disease outcomes (improvement in renal functions, relapse rates, and survival) were similar in both groups. However, those receiving methylprednisolone pulses had 2.7 greater risk of serious infections, and 6.3 times the risk of developing dysglycemia, compared to the control group.[29] The adverse effects of long-term corticosteroid therapy are also an emerging concern in AAV[30],[31] and shall be discussed in detail later in this review. Contemporary approaches have investigated the role of paucisteroid regimens for remission induction in AAV. A cohort of 49 patients with AAV were treated with intravenous rituximab (1 g, two doses, at 1–2 week intervals), low-dose intravenous cyclophosphamide (500–750 mg at 2 week intervals for six doses), with 1–2 doses of intravenous methylprednisolone pulses at onset followed by oral corticosteroids for only 1–2 weeks. Ninety-six percent patients had attained remission at 6 months, and 90% at 12 months, without needing rescue corticosteroid therapy. Three patients died, and two relapsed during the 1st-year. Results were comparable with historical data from EUVAS trials,[32] although concerns remained that the patients in this cohort might have had a milder disease phenotype,[33] and there might have been overestimation of remission rates.[34] The SCOUT study analyzed outcomes at 6 months in 20 patients with active AAV treated with four weekly doses of rituximab, along with fixed-dose tapering corticosteroids with stoppage by 8 weeks. 70% patients attained remission at 6 months, comparable with results from matched patients from the RAVE trial. However, nearly a third had relapsed during this period (compared to 7% in the RAVE trial).[35] A third study evaluated a novel molecule, avacopan, which blocks the C5a receptor, in the CLEAR study. In this randomized trial, 23 patients with active AAV received prednisolone 60 mg daily with placebo, another 22 received avacopan 30 mg twice daily with a lower dose of prednisolone 20 daily, and a third group of 22 patients received avacopan alone at the same dose. At 12 weeks, 70% in the prednisolone only group, 86% in the combined group, and 81% in the avacopan alone group attained remission. Similar improvements in renal functions and quality of life, and similar accrual of damage, were noted across the three groups.[36] Avacopan is further being investigated in an ongoing Phase III study (the ADVOCATE study).[2] While these studies hint at the feasibility of corticosteroid-light or corticosteroid-free regimens, the exact utility, including the specific situations of milder disease or with agents such as avacopan, where this may have a role to play, remain to be explored, and are the subject of ongoing clinical trials.[33]

Ancillary therapeutic modalities like plasma exchange (PLEX) are indicated in AAV with severe renal or pulmonary involvement. A retrospective analysis of 94 patients with AAV treated with PLEX reported renal recovery to a stage of dialysis independence in two-thirds and survival at 1-year and 5 years of 75% and 61% patients.[37] Another large retrospective multicentric case series of 152 patients from France treated with PLEX (126 for rapidly progressive renal failure due to glomerulonephritis, 64 for diffuse alveolar hemorrhage, and 23 for mononeuritis multiplex) reported significant improvements in renal functions over time, freedom from ventilatory support for patients with all 15 patient with alveolar hemorrhage, recovery of motor function in patients with neuropathy, and survival of 88% at 22 months.[38] The full results of a randomized controlled study assessing the utility of PLEX in AAV (the PEXIVAS study) are still awaited.[2] Intravenous immunoglobulin (IVIG) remains a therapeutic option in patients unable to be treated with high-dose corticosteroids or other immunosuppressive therapy due to concomitant infections. A recent systematic review of > 180 patients with AAV treated with IVIG reaffirmed its usefulness in inducing remission in active AAV.[39] Omalizumab, a monoclonal antibody to IgE approved for use in asthma, also demonstrated steroid-sparing efficacy in 18 patients with EGPA in a retrospective study.[40]

Patients with AAV with respiratory involvement may require ventilatory support during periods of active disease or infection. Recent literature supports the use of extracorporeal membrane oxygenation (ECMO) in such patients. In this paper, which analyzed 14 published cases of ECMO in the background of AAV, all the reported patients had favorable outcomes. Despite theoretical concerns that there may be increased risk of pulmonary bleeds in such patients due to the systemic anticoagulation state resulting from ECMO, none of these 14 patients developed this complication and only three developed bleeding manifestations elsewhere (two had major bleeds).[41]

  Remission Maintenance in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Top

Classically, maintenance regimens used in AAV have used azathioprine, methotrexate, or MMF. In an Italian study of 71 AAV patients randomized to receive maintenance therapy with methotrexate (n = 38) or oral cyclophosphamide (n = 33) for a year after attaining remission, there were no differences noted in relapse rates at 1-year (9/38 vs. 7/33) or at 2 years (12/38 vs. 13/33) after enrollment in the study, suggesting similar efficacy of the two agents in maintaining remission.[42] An older study evaluated the role of maintenance therapy in AAV with MMF in 76 patients) compared to azathioprine (in 80 patients) in an open-label randomized trial. Followed up over a median 39 months, there was a significantly greater risk of relapse with MMF compared to azathioprine (HR 1.69, 95% CI 1.06–2.70).[43] However, another retrospective, uncontrolled study of 67 patients with AAV from Spain reported favorable maintenance of remission with MMF (median dose [1000 mg] over 2 years), with retention of 82% patients on the drug at 2 years, and relapses in 6/67 patients during this period.[44]

The WEGENT trial had compared maintenance with methotrexate compared to azathioprine in 126 patients with AAV (97 GPA, 29 MPA; 63 in each group), and long-term follow-up data of this study was recently published (median duration of follow-up 7.7 years for azathioprine compared to 5 years for methotrexate). Long-term survival rates at 10 years (75.1% for azathioprine, and 79.9% for methotrexate), as well as proportions of relapses (60% for azathioprine, 54% for methotrexate) were comparable between the groups, suggesting similar long-term results with either treatment. Positivity for PR3 ANCA associated with nearly two times greater relapse risk, whereas higher dose of corticosteroid at the end of maintenance treatment, longer duration of corticosteroid therapy, and lower baseline serum creatinine were all associated with a small but significantly greater risk of relapse. PR3 ANCA, duration of glucocorticoid therapy, advancing age and higher baseline serum creatinine associated with the development of damage.[45] Overall, azathioprine remains the conventional immunosuppressant of choice for maintaining remission in AAV.

The duration of maintenance therapy remains a matter of active debate. Three recent studies addressed the duration of azathioprine maintenance therapy in AAV. Three hundred and eighty-four patients (236 GPA, 136 MPA) with AAV previously recruited in multiple clinical trials by the EUVAS, followed up for a median of 65 months, were retrospectively analyzed for the duration of azathioprine maintenance therapy. When duration of azathioprine maintenance for up to 12 months was compared with those receiving the drug for more than a year, the former group had a greater risk of relapse (HR 0.57, 95% CI 0.35–0.94). However, no such distinction was evident from this retrospective analysis for a period of azathioprine therapy up to 18 months compared with >18 months.[46] In a prospective multicentric study from the Netherlands, 45 patients with PR3 AAV were randomized to receive azathioprine maintenance (1.5–2 mg/kg/day) for 1-year (24 patients) or for 4 years (21 patients), followed by initiation of azathioprine taper by 25 mg 3 monthly. Although numerically the proportions of patients relapsing in the former group (46%) was higher than in the second group (24%), the difference was not statistically significant.[47] A third study (the REMAIN study) randomized 117 patients with AAV in stable remission at 18–24 months after diagnosis to either taper azathioprine starting at 24 months (56 patients) or continue it until 48 months without taper (61 patients). Withdrawal of azathioprine at 24 months was associated with a 5.96 greater odds of relapse (95% CI 2.58–13.77) compared to the group continuing azathioprine till 48 months.[48]

The landscape of maintenance regimens in AAV has been revolutionized in the past 5 years with the advent of rituximab-based maintenance regimens. The MAINRITSAN trial was the first such attempt to evaluate rituximab compared to azathioprine as a maintenance agent. 115 patients with AAV (87 GPA, 23 MPA, and 5 renal-limited vasculitis), in whom remission had previously been induced with cyclophosphamide and corticosteroids, were randomized to receive either two doses of 500 mg rituximab at 2-week intervals, followed by 6 monthly single intravenous dose of rituximab for 18 months (58 patients), or azathioprine 2 mg/kg/day for 12 months, then 1.5 mg/kg/day for 6 months, and 1 mg/kg/day for 4 months (57 patients). The primary end point, i.e., relapse at month 28, occurred in 5% patients on rituximab compared to 29% patients on azathioprine, and the HR for relapse with azathioprine compared to rituximab was 6.61 (95% CI 1.56–27.96), with similar adverse effect profile.[49] At 24 months, the quality of life parameters were also better in the rituximab treated patients, compared to those on azathioprine.[50] A longer term follow-up of this cohort was recently published. At 60 months, the risk of major relapse free survival was 71.9% in the rituximab arm, compared to 49.4% in the azathioprine arm, and that of major and minor relapse-free survival was 57.9% for rituximab versus 37.2% for azathioprine; rituximab-treated patients relapsed a year later than those treated with azathioprine, suggesting better long-term outcomes with rituximab maintenance.[51] Subsequently, the question arose as to whether rituximab had to be dosed as per the fixed regimen used in MAINRITSAN for maintenance of remission, or whether the dosing could be tailored according to repletion of B-lymphocytes or reappearance/marked increase of titers of ANCA without clinical relapse (tailored regimen), in the MAINRITSAN 2 trial. In this trial, 162 patients (117 GPA and 45 MPA) were randomized (81 each) to the fixed-dose regimen or tailored regimen for rituximab administration over 18 months. Relapse rates were similar at 28 months (17.3% in the tailored regimen vs. 9.9% in the fixed-dose regimen), and the median number of infusions (95% CI) was lesser in the tailored regimen (32–4 vs. 55–5). This trial suggested the feasibility of limiting exposure to rituximab in maintenance regimens without compromising on long-term outcomes in AAV.[52] The important observation in this study was that the relapses occurred even in patient with absent circulating B-cells, probably due to active B-cell population at site of inflammation, and also for the fact that CD19 lymphocyte count is not strictly associated with CD27-positive memory B-cell reemergence. There are concerns regarding the sample size calculation for this study, which took the figure of 35% relapse rates in the control group for sample size calculation without any particular justification for the same, whereas, in reality, only 5% patients had major relapses and 11% minor relapses. The other concern was that, even though the higher total and major relapses in the tailored arm were not significant during the follow-up period presented in the paper, these might have become significant on a long-term follow-up.[53] The reason for this sample size calculation was likely due to the planning of MAINRITSAN 2 study being conducted before the availability of MAINRITSAN study results (which had much lesser relapses on rituximab).[54]

Future studies might evaluate the feasibility of doses of rituximab lower than the standard 375 mg/m2, which has been shown to deplete B-lymphocytes significantly in healthy individuals.[55] Ongoing studies are assessing whether duration of rituximab infusions for maintenance therapy for 18 months or 46 months may be similarly efficacious (MAINRITSAN 3 trial).[2] Another important emerging concept refers to the differential kinetics of B-lymphocyte repopulation following rituximab infusions in AAV when compared to other diseases where rituximab is commonly used, such as rheumatoid arthritis (RA), lupus, or other connective tissue diseases (CTD). In a retrospective analysis of B-lymphocyte counts following rituximab therapy in routine practice, 10% patients with AAV showed repopulation of B-cells by 1-year (as opposed to nearly 90% in other disease settings). A single infusion of rituximab depleted B-lymphocytes for a median of 21–26 months in AAV, compared with 8–9 months in RA or CTDs.[56]

Recent interest has grown in the potential use of belimumab (antagonist of B-cell activating factor), and a recent randomized controlled trial (the BREVAS study) evaluated the role of add-on belimumab at 10 mg/kg (intravenous, at 0, 14, and 28 days, thereafter every 28 days) (52 patients) or placebo (52 patients), both groups receiving low-dose corticosteroids and azathioprine 2 mg/kg/day for maintenance therapy after initial induction of remission with cyclophosphamide (78) or rituximab (27). There was no difference between groups in the proportions of patients attaining a prespecified outcome (taken as a composite of major relapses, treatment failures, or requirement of other medications for maintaining remission – 21.2% in placebo vs. 18.9% in belimumab groups), or in the proportions of relapses (15.4% in placebo vs. 11.3% in belimumab groups). Thus, no add-on benefit of using belimumab could be demonstrated for the maintenance of remission in AAV, although no particular safety concerns could be identified.[57]

  Long-Term Outcomes, and Their Prediction, in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Top

With increasing recognition of AAV as a distinct entity, more patients are being diagnosed in the past two decades than in the last two decades of the past century. Over time, the median survival of patients with AAV has also increased, based on data from the UK (59 months vs. 125 months for patients diagnosed before or after 2000).[58] Therefore, it is natural that recent literature has focused on long-term outcomes and their determinants in patients with AAV. An analysis of more than 530 patients enrolled in EUVAS trials, and followed up over 7 years revealed the common damage items (i.e., clinical features, either related to the disease per se, or related to drugs used for treatment, which are unlikely to reverse with further treatment), at both the time points of 6 months and 7 years, were renal (persistent proteinuria, elevation of serum creatinine, and hypertension), respiratory (hearing impairment, and nasal crusts), and neurological (peripheral neuropathy). At the time period of 7 years, the most common drug-related damage items were dysglycemia, hypertension, osteoporosis, and malignancies.[31] Another analysis of EUVAS trials data specifically analyzed damage in AAV from viewpoint of glucocorticoid use. For 296 AAV patients with data available at 7 years (although a significant number did not have data regarding these variables at these time points), the items related to greater damage were exposure to higher cumulative doses of glucocorticoids, older age, worse baseline renal function, and greater number of relapses. Every year of glucocorticoid therapy increased the odds of having a vasculitis damage index score of 5 or more by 1.26 times (95% CI 1.03–1.53).[30] In this context, strategies assessing minimization of exposure to glucocorticoids over time in AAV patients, as discussed earlier, are increasingly relevant.[32],[36] A further analysis of long-term follow-up data (median 5.7 years) from the EUVAS trials reported prediction of long-term outcomes with disease status in the first 6 months of diagnosis. Those with attainment of disease activity remission after 3 months but by 6 months, relapses of disease by 6 months after initially attaining remission at 3 months, and inability to attain remission by 6 months (refractory disease) had 2.94, 8.21, and 4.89 greater HR, respectively, of developing either ESRD or death during this follow-up period.[59] Secondary analysis of data from the RAVE trial indicated that not just glucocorticoid use, but also improvements in disease activity status and rituximab therapy also independently associated with increases in body mass index of patients on follow-up.[60] This may require further attention, given that cardiovascular risk factors are already increased in AAV patients in the longer term.[31] Since progression to ESRD remains a major concern in AAV with renal involvement, scoring algorithms have been proposed to predict long-term renal outcomes from baseline characteristics. A clinicopathologic score, ranging from 0 to 11, was developed and validated in >200 patients with AAV with renal involvement, taking into consideration the proportions of normal-appearing glomeruli, percentage of tubule-interstitial changes (atrophy/fibrosis), and baseline estimated glomerular filtration rate. This score could predict progression to ESRD in 36 months, in none of the patients if score was 0, 26%–27% if score was between 2 and 7, and 68%–78% if the score ranged from 8 to 11.[61] Although patients with AAV and renal involvement often require renal replacement therapy (RRT) with hemodialysis at diagnosis, a significant proportion of patients eventually attain sufficient recovery of their compromised renal function to come off RRT. A recent paper analyzed histopathological predictors of dialysis dependence in 40 patients with AAV requiring dialysis initially. The authors reported that the proportion of glomeruli showing fibrous crescents or global glomerular sclerosis could predict dependence or recovery from hemodialysis. If this proportion was >32.6%, then dialysis dependence could be predicted with 93% sensitivity and 88% specificity, whereas a proportion >47.9% predicted uniformly dialysis dependence. Further, recovery of renal function was faster in those patients receiving PLEX.[62] Histopathological classification of pauci-immune glomerulonephritis was developed to help in prognostication of these patients. The renal glomerular changes were classified into focal, crescentic, sclerotic, or mixed classes. Focal and crescentic classes of glomerulonephritis were shown to have better outcomes, while the sclerotic class had worst outcomes.[63],[64] Other recent studies have utilized clinical parameters at baseline (lymphocyte count, hemoglobin, and serum creatinine levels)[65] and gene expression signature of multiple genes[66] to predict long-term outcomes in AAV. However, these various indices remain to be validated across populations. It is reasonable to suppose that these indices would remain population-specific and such population-specific indices would require to be developed separately for different ethnicities and geographic regions.

Immunosuppressive regimens used in these patients heighten the risk of infections. A recent paper from Sweden analyzed infection rates in 186 AAV patients compared to healthy controls, and identified the most common infections to be upper respiratory tract infections, systemic sepsis, intestinal infection with clostridium difficile, and skin infections. The overall rate ratio for developing severe infections in AAV patients was 4.53, which were most common in the first 6 months (38%), then similarly distributed between the time periods of 7–24 months and after 24 months of diagnosis.[67] Those with older age at diagnosis, or higher baseline serum creatinine at diagnosis, had a greater predisposition to severe infections, and those developing severe infections nearly had twice the risk of mortality.[67] In this context, another recent retrospective analysis of 192 AAV patients from two tertiary care centers in Austria and the UK reported the rate of severe infections as 26/100 patient-years; nearly two-thirds were respiratory infections. Use of cotrimoxazole prophylaxis significantly reduced the risk of serious infections (HR 0.3, 95% CI 0.13–0.69), whereas the presence of older age, endobronchial involvement due to disease, presence of concomitant chronic obstructive airway disease, and use of the rescue agent alemtuzumab significantly increased the risk of serious infections.[68] Considering the significant proportions of respiratory infections in these patients, the importance of vaccinating such patients with pneumococcal and influenza vaccines cannot be adequately emphasized. Recent literature, albeit from studies of small numbers of patients with AAV, have focused on the timing of such vaccines. A study of 19 patients with AAV (10 who received pneumococcal vaccine during disease remission while on maintenance immunosuppression or no therapy and 9 who were vaccinated while continuing intensive immunosuppressive therapy – glucocorticoids with cyclophosphamide/rituximab – for disease remission induction), assessed the effectiveness of such vaccination in generating protective antibody titers. Seven out of ten patients in the former group developed protective antibody titers, as compared to a single patient out of nine in the latter group.[69] Another study reported effective vaccination with trivalent influenza strain in patients with AAV in remission.[70] These studies emphasize that patients with AAV should be vaccinated preferably at the earliest time after diagnosis if there seems to be a consideration for significant immunosuppressive therapy during their disease course, or during a period of quiescent disease in those not previously vaccinated. However, the administration of cyclophosphamide or rituximab in patients with severe AAV should not be delayed simply because a patient has not been vaccinated previously.[71] With the increasing use of rituximab in AAV settings, hypogammaglobulinemia is an increasingly recognized complication, with a greater risk of developing hypogammaglobulinemia in those with already low IgG levels at baseline (<6 g/L), prior exposure to cyclophosphamide therapy (10 g or more), and the concomitant use of other immunosuppressive agents such as cumulative corticosteroid exposure. However, repeated rituximab infusions per se, in the absence of these risk factors, do not seem to confer risk of hypogammaglobulinemia. The median time to the development of hypogammaglobulinemia in those with normal baseline levels was 18 months (range 1–65 months), and nadir levels of such hypogammaglobulin levels were obtained by 35 months (range 1–70 months). Varying recommendations exist for immunoglobulin replacement therapy in such patients, with levels <5 g/L along with absence of protective antibody titers to infections, and recurrent infections despite 3 months of prophylactic antibiotic therapy. Such immunoglobulin replacement is generally initiated at a dose of 0.4 g/kg/month and titrated to maintain trough levels above the reference range for hypogammaglobulinemia. Such patients should not receive live vaccines.[72]

Increased risk of developing malignancies remains another long-term concern in AAV patients (standardized incidence ratio of 1.89, 95% CI 1.38–2.53). Emerging evidence, from a cohort of 323 patients with AAV from the UK followed up over 1802 patient-years, suggests that use of cyclophosphamide confers a greater risk of developing malignancy in the longer term than rituximab (relative risk 4.61, 95% CI 1.16–39.98). The most common malignancies were nonmelanoma skin cancers, and EGPA conferred the greatest absolute risk of developing malignancy, followed by GPA and MPA.[73]

  Guidelines for Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Management Top

In the past 5 years, society guidelines for the management of AAV have been published from the British Society for Rheumatology,[74] European League against Rheumatism,[75] Canadian Vasculitis Society,[76] Brazilian Society of Rheumatology,[77] and the Japanese Ministry for health.[78] The major recommendations of these guidelines are comparatively presented in [Table 1]. Overall, most of them recommend remission induction with either cyclophosphamide or rituximab in severe disease, with methotrexate and MMF as alternatives in those with milder disease. Azathioprine, rituximab, methotrexate, or MMF is suitable agents for maintenance of remission, with various societies recommending a duration of maintenance therapy for 18–24 months after remission induction. Adequate attention must also be paid toward vaccination, cotrimoxazole prophylaxis, and assessment of long-term damage, including heightened cardiovascular risk in these patients.
Table 1: Comparison of different guidelines for management of antineutrophil cytoplasmic antibody-associated vasculitis

Click here to view

  Conclusion Top

While most of the information regarding the management of AAV has been derived from multiple randomized controlled trials, it must be kept in mind that patients with AAV enrolled in clinical trials of AAV were found to be older, as well as had more severe disease, greater proprotions of renal involvement, lesser upper airway disease (considered a favorable prognostic factor), and worse long-term outcomes (relapses, and mortality) when compared to patients from case series of AAV drawn from the real-world settings. This may suggest that such patients enrolled in clinical trials had a more severe disease phenotype.[79] Overall, the prognosis of AAV has improved with time, and regimens associated with lesser toxicity are coming into vogue, for both remission induction and maintenance. However, the optimal dosing of rituximab for induction and dosing intervals for maintenance are still under active investigation. Increasingly, corticosteroid use, despite its obvious short-term benefits in this devastating disease, is being recognized as a major contributor to long-term morbidity, and paucisteroid regimens are being evaluated, including the use of novel agents such as avacopan to avoid using corticosteroids. Infection prophylaxis, with prophylactic cotrimoxazole use, and timely vaccination with killed vaccines, remains an important consideration in such patients. Recent guidelines for AAV management from different societies worldwide provide standardized recommendations for the management of this once uniformly fatal disease. [Table 2] summarizes areas of ongoing or potential future research in the management of AAV.
Table 2: Avenues for future research in antineutrophil cytoplasmic antibody-associated vasculitis management

Click here to view

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised international chapel hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013;65:1-11.  Back to cited text no. 1
Misra DP, Naidu GS, Agarwal V, Sharma A. Vasculitis research: Current trends and future perspectives. Int J Rheum Dis 2019;22 Suppl 1:10-20.  Back to cited text no. 2
Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD. Writing a narrative biomedical review: Considerations for authors, peer reviewers, and editors. Rheumatol Int 2011;31:1409-17.  Back to cited text no. 3
de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: A randomized trial. Ann Intern Med 2009;150:670-80.  Back to cited text no. 4
Harper L, Morgan MD, Walsh M, Hoglund P, Westman K, Flossmann O, et al. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: Long-term follow-up. Ann Rheum Dis 2012;71:955-60.  Back to cited text no. 5
La-Crette J, Royle J, Lanyon PC, Ferraro A, Butler A, Pearce FA. Long-term outcomes of daily oral vs. pulsed intravenous cyclophosphamide in a non-trial setting in ANCA-associated vasculitis. Clin Rheumatol 2018;37:1085-90.  Back to cited text no. 6
Sharma A, Naidu GS, Rathi M, Verma R, Modi M, Pinto B, et al. Clinical features and long-term outcomes of 105 granulomatosis with polyangiitis patients: A single center experience from North India. Int J Rheum Dis 2018;21:278-84.  Back to cited text no. 7
Pagnoux C, Quéméneur T, Ninet J, Diot E, Kyndt X, de Wazières B, et al. Treatment of systemic necrotizing vasculitides in patients aged sixty-five years or older: Results of a multicenter, open-label, randomized controlled trial of corticosteroid and cyclophosphamide-based induction therapy. Arthritis Rheumatol 2015;67:1117-27.  Back to cited text no. 8
Tuin J, Stassen PM, Bogdan DI, Broekroelofs J, van Paassen P, Cohen Tervaert JW, et al. Mycophenolate mofetil versus cyclophosphamide for the induction of remission in nonlife-threatening relapses of antineutrophil cytoplasmic antibody-associated vasculitis: Randomized, controlled trial. Clin J Am Soc Nephrol 2019;14:1021-8.  Back to cited text no. 9
Jones RB, Hiemstra TF, Ballarin J, Blockmans DE, Brogan P, Bruchfeld A, et al. Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: A randomised, non-inferiority trial. Ann Rheum Dis 2019;78:399-405.  Back to cited text no. 10
Jain S, Chattopadhyay A, Naidu S, Sharma A. MYCYC: Unravelling the long road ahead in ANCA-associated vasculitis. Ann Rheum Dis 2019. pii: Annrheumdis-2019-215241.  Back to cited text no. 11
Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363:221-32.  Back to cited text no. 12
Geetha D, Specks U, Stone JH, Merkel PA, Seo P, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis with renal involvement. J Am Soc Nephrol 2015;26:976-85.  Back to cited text no. 13
Miloslavsky EM, Specks U, Merkel PA, Seo P, Spiera R, Langford CA, et al. Outcomes of nonsevere relapses in antineutrophil cytoplasmic antibody-associated vasculitis treated with glucocorticoids. Arthritis Rheumatol 2015;67:1629-36.  Back to cited text no. 14
Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010;363:211-20.  Back to cited text no. 15
Jones RB, Furuta S, Tervaert JW, Hauser T, Luqmani R, Morgan MD, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial. Ann Rheum Dis 2015;74:1178-82.  Back to cited text no. 16
Ayan G, Esatoglu SN, Hatemi G, Ugurlu S, Seyahi E, Melikoglu M, et al. Rituximab for anti-neutrophil cytoplasmic antibodies-associated vasculitis: Experience of a single center and systematic review of non-randomized studies. Rheumatol Int 2018;38:607-22.  Back to cited text no. 17
Joshi L, Tanna A, McAdoo SP, Medjeral-Thomas N, Taylor SR, Sandhu G, et al. Long-term outcomes of rituximab therapy in ocular granulomatosis with polyangiitis: Impact on localized and nonlocalized disease. Ophthalmology 2015;122:1262-8.  Back to cited text no. 18
Lally L, Lebovics RS, Huang WT, Spiera RF. Effectiveness of rituximab for the otolaryngologic manifestations of granulomatosis with polyangiitis (Wegener's). Arthritis Care Res (Hoboken) 2014;66:1403-9.  Back to cited text no. 19
Sharma A, Mittal S, Naidu G, Jha S, Rathi M, Sharma V, et al. Efficacy and safety of biomimic rituximab in granulomatosis with polyangiitis-Experience from a single tertiary care centre in India [abstract]. Arthritis Rheumatol 2018;70 Suppl 10.  Back to cited text no. 20
Mohammad AJ, Hot A, Arndt F, Moosig F, Guerry MJ, Amudala N, et al. Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg-strauss). Ann Rheum Dis 2016;75:396-401.  Back to cited text no. 21
Thiel J, Troilo A, Salzer U, Schleyer T, Halmschlag K, Rizzi M, et al. Rituximab as induction therapy in eosinophilic granulomatosis with polyangiitis refractory to conventional immunosuppressive treatment: A 36-month follow-up analysis. J Allergy Clin Immunol Pract 2017;5:1556-63.  Back to cited text no. 22
Takakuwa Y, Hanaoka H, Kiyokawa T, Iida H, Fujimoto H, Yamasaki Y, et al. Low-dose rituximab as induction therapy for ANCA-associated vasculitis. Clin Rheumatol 2019;38:1217-23.  Back to cited text no. 23
Turner-Stokes T, Sandhu E, Pepper RJ, Stolagiewicz NE, Ashley C, Dinneen D, et al. Induction treatment of ANCA-associated vasculitis with a single dose of rituximab. Rheumatology (Oxford) 2014;53:1395-403.  Back to cited text no. 24
McAdoo SP, Bedi R, Tarzi R, Griffith M, Pusey CD, Cairns TD. Ofatumumab for B cell depletion therapy in ANCA-associated vasculitis: A single-centre case series. Rheumatology (Oxford) 2016;55:1437-42.  Back to cited text no. 25
McAdoo SP, Medjeral-Thomas N, Gopaluni S, Tanna A, Mansfield N, Galliford J, et al. Long-term follow-up of a combined rituximab and cyclophosphamide regimen in renal anti-neutrophil cytoplasm antibody-associated vasculitis. Nephrol Dial Transplant 2019;34:63-73.  Back to cited text no. 26
Cortazar FB, Muhsin SA, Pendergraft WF 3rd, Wallace ZS, Dunbar C, Laliberte K, et al. Combination therapy with rituximab and cyclophosphamide for remission induction in ANCA vasculitis. Kidney Int Rep 2018;3:394-402.  Back to cited text no. 27
Lionaki S, Fragoulis GE, Venetsanopoulou A, Vlachoyiannopoulos P, Boletis JN, Tzioufas AG. Cyclophosphamide followed by rituximab for aggressive multiple-relapsing antineutrophil cytoplasmic antibody-associated vasculitis. Clin Exp Rheumatol 2017;35 Suppl 103:155-64.  Back to cited text no. 28
Chanouzas D, McGregor JA, Nightingale P, Salama AD, Szpirt WM, Basu N, et al. Intravenous pulse methylprednisolone for induction of remission in severe ANCA associated vasculitis: A multi-center retrospective cohort study. BMC Nephrol 2019;20:58.  Back to cited text no. 29
Robson J, Doll H, Suppiah R, Flossmann O, Harper L, Höglund P, et al. Glucocorticoid treatment and damage in the anti-neutrophil cytoplasm antibody-associated vasculitides: Long-term data from the European vasculitis study group trials. Rheumatology (Oxford) 2015;54:471-81.  Back to cited text no. 30
Robson J, Doll H, Suppiah R, Flossmann O, Harper L, Höglund P, et al. Damage in the anca-associated vasculitides: Long-term data from the European vasculitis study group (EUVAS) therapeutic trials. Ann Rheum Dis 2015;74:177-84.  Back to cited text no. 31
Pepper RJ, McAdoo SP, Moran SM, Kelly D, Scott J, Hamour S, et al. Anovel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford) 2019;58:260-8.  Back to cited text no. 32
Patro P, Agarwal V, Misra DP. Comment on: A novel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford) 2019;58:1117-9.  Back to cited text no. 33
Jain S, Naidu GS, Dhir V, Jain S, Sharma A. Comment on: A novel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford) 2019;58:737-8.  Back to cited text no. 34
Miloslavsky EM, Niles JL, Wallace ZS, Cortazar FB, Fernandes A, Laliberte K, et al. Reducing glucocorticoid duration in ANCA-associated vasculitis: A pilot trial. Semin Arthritis Rheum 2018;48:288-92.  Back to cited text no. 35
Jayne DR, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol 2017;28:2756-67.  Back to cited text no. 36
Frausová D, Hrušková Z, Lánská V, Lachmanová J, Tesař V. Long-term outcome of patients with ANCA-associated vasculitis treated with plasma exchange: A retrospective, single-centre study. Arthritis Res Ther 2016;18:168.  Back to cited text no. 37
de Luna G, Chauveau D, Aniort J, Carron PL, Gobert P, Karras A, et al. Plasma exchanges for the treatment of severe systemic necrotizing vasculitides in clinical daily practice: Data from the french vasculitis study group. J Autoimmun 2015;65:49-55.  Back to cited text no. 38
Shimizu T, Morita T, Kumanogoh A. The therapeutic efficacy of intravenous immunoglobulin in anti-neutrophilic cytoplasmic antibody-associated vasculitis: A meta-analysis. Rheumatology (Oxford) 2019. pii: kez311.  Back to cited text no. 39
Celebi Sozener Z, Gorgulu B, Mungan D, Sin BA, Misirligil Z, Aydin O, et al. Omalizumab in the treatment of eosinophilic granulomatosis with polyangiitis (EGPA): Single-center experience in 18 cases. World Allergy Organ J 2018;11:39.  Back to cited text no. 40
Delvino P, Monti S, Balduzzi S, Belliato M, Montecucco C, Caporali R. The role of extra-corporeal membrane oxygenation (ECMO) in the treatment of diffuse alveolar haemorrhage secondary to ANCA-associated vasculitis: Report of two cases and review of the literature. Rheumatol Int 2019;39:367-75.  Back to cited text no. 41
Maritati F, Alberici F, Oliva E, Urban ML, Palmisano A, Santarsia F, et al. Methotrexate versus cyclophosphamide for remission maintenance in ANCA-associated vasculitis: A randomised trial. PLoS One 2017;12:e0185880.  Back to cited text no. 42
Hiemstra TF, Walsh M, Mahr A, Savage CO, de Groot K, Harper L, et al. Mycophenolate mofetil vs. azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: A randomized controlled trial. JAMA 2010;304:2381-8.  Back to cited text no. 43
Draibe J, Poveda R, Fulladosa X, Vidaller A, Zulberti C, GomàM, et al. Use of mycophenolate in ANCA-associated renal vasculitis: 13 years of experience at a university hospital. Nephrol Dial Transplant 2015;30 Suppl 1:i132-7.  Back to cited text no. 44
Puéchal X, Pagnoux C, Perrodeau É, Hamidou M, Boffa JJ, Kyndt X, et al. Long-term outcomes among participants in the WEGENT trial of remission-maintenance therapy for granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis. Arthritis Rheumatol 2016;68:690-701.  Back to cited text no. 45
de Joode AA, Sanders JS, Puéchal X, Guillevin LP, Hiemstra TF, Flossmann O, et al. Long term azathioprine maintenance therapy in ANCA-associated vasculitis: Combined results of long-term follow-up data. Rheumatology (Oxford) 2017;56:1894-901.  Back to cited text no. 46
Sanders JS, de Joode AA, DeSevaux RG, Broekroelofs J, Voskuyl AE, van Paassen P, et al. Extended versus standard azathioprine maintenance therapy in newly diagnosed proteinase-3 anti-neutrophil cytoplasmic antibody-associated vasculitis patients who remain cytoplasmic anti-neutrophil cytoplasmic antibody-positive after induction of remission: A randomized clinical trial. Nephrol Dial Transplant 2016;31:1453-9.  Back to cited text no. 47
Karras A, Pagnoux C, Haubitz M, Groot K, Puechal X, Tervaert JW, et al. Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis. Ann Rheum Dis 2017;76:1662-8.  Back to cited text no. 48
Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaître O, Cohen P, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 2014;371:1771-80.  Back to cited text no. 49
Pugnet G, Pagnoux C, Terrier B, Perrodeau E, Puéchal X, Karras A, et al. Rituximab versus azathioprine for ANCA-associated vasculitis maintenance therapy: Impact on global disability and health-related quality of life. Clin Exp Rheumatol 2016;34:S54-9.  Back to cited text no. 50
Terrier B, Pagnoux C, Perrodeau É, Karras A, Khouatra C, Aumaître O, et al. Long-term efficacy of remission-maintenance regimens for ANCA-associated vasculitides. Ann Rheum Dis 2018;77:1150-6.  Back to cited text no. 51
Charles P, Terrier B, Perrodeau É, Cohen P, Faguer S, Huart A, et al. Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: Results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). Ann Rheum Dis 2018;77:1143-9.  Back to cited text no. 52
Chattopadhyay A, Acharya N, Mishra D, Sharma V, Naidu G, Sharma A, et al. 'MAINRITSAN2-the future', with some doubts! Ann Rheum Dis 2018. pii: annrheumdis-2018-214486.  Back to cited text no. 53
Charles P, Guillevin L. Response to: '“MAINRITSAN2-the future”, with some doubts!' by chattopadhyay et al. Ann Rheum Dis 2018. pii: annrheumdis-2018-214516.  Back to cited text no. 54
Moiseev SV, Bulanov NM, Zykova AS, Novikov PI. Rituximab in ANCA-associated vasculitis: Fewer infusions or ultra low-dose maintenance therapy? Ann Rheum Dis 2019;78:e99.  Back to cited text no. 55
Thiel J, Rizzi M, Engesser M, Dufner AK, Troilo A, Lorenzetti R, et al. Bcell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides compared to rheumatoid arthritis, and connective tissue diseases: A longitudinal observational study on 120 patients. Arthritis Res Ther 2017;19:101.  Back to cited text no. 56
Jayne D, Blockmans D, Luqmani R, Moiseev S, Ji B, Green Y, et al. Efficacy and safety of belimumab and azathioprine for maintenance of remission in antineutrophil cytoplasmic antibody-associated vasculitis: A randomized controlled study. Arthritis Rheumatol 2019;71:952-63.  Back to cited text no. 57
Whatmough S, Fernandez S, Sweeney N, Howell L, Dhaygude A. Comparing outcomes of biopsy-proven anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis patients treated with cyclophosphamide in the 20th and 21st centuries: A 23-year study. Clin Kidney J 2019;12:42-8.  Back to cited text no. 58
Gopaluni S, Flossmann O, Little MA, O'Hara P, Bekker P, Jayne D, et al. Effect of disease activity at three and six months after diagnosis on long-term outcomes in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol 2019;71:784-91.  Back to cited text no. 59
Wallace ZS, Miloslavsky EM, Cascino M, Unizony SH, Lu N, Hoffman GS, et al. Effect of disease activity, glucocorticoid exposure, and rituximab on body composition during induction treatment of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Care Res (Hoboken) 2017;69:1004-10.  Back to cited text no. 60
Brix SR, Noriega M, Tennstedt P, Vettorazzi E, Busch M, Nitschke M, et al. Development and validation of a renal risk score in ANCA-associated glomerulonephritis. Kidney Int 2018;94:1177-88.  Back to cited text no. 61
Xu PC, Chen T, Wu SJ, Yang X, Gao S, Hu SY, et al. Pathological severity determines the renal recovery for anti-myeloperoxidase antibody-associated vasculitis requiring dialysis at disease onset: A retrospective study. BMC Nephrol 2019;20:287.  Back to cited text no. 62
Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K, et al. Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol 2010;21:1628-36.  Back to cited text no. 63
Naidu GS, Sharma A, Nada R, Kohli HS, Jha V, Gupta KL, et al. Histopathological classification of pauci-immune glomerulonephritis and its impact on outcome. Rheumatol Int 2014;34:1721-7.  Back to cited text no. 64
Kim MK, Choi H, Kim JY, Song JJ, Park YB, Lee SW. Multivariable index for assessing the activity and predicting all-cause mortality in antineutrophil cytoplasmic antibody-associated vasculitis. J Clin Lab Anal 2019:e23022.  Back to cited text no. 65
Ishizu A, Tomaru U, Masuda S, Sada KE, Amano K, Harigai M, et al. Prediction of response to remission induction therapy by gene expression profiling of peripheral blood in Japanese patients with microscopic polyangiitis. Arthritis Res Ther 2017;19:117.  Back to cited text no. 66
Mohammad AJ, Segelmark M, Smith R, Englund M, Nilsson JŠ, Westman K, et al. Severe infection in antineutrophil cytoplasmic antibody-associated vasculitis. J Rheumatol 2017;44:1468-75.  Back to cited text no. 67
Kronbichler A, Kerschbaum J, Gopaluni S, Tieu J, Alberici F, Jones RB, et al. Trimethoprim-sulfamethoxazole prophylaxis prevents severe/life-threatening infections following rituximab in antineutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis 2018;77:1440-7.  Back to cited text no. 68
Groh M, Puéchal X, Terrier B, Le Jeunne C, Batteux F, Launay O. Failure of pneumococcal immunization during remission induction treatment of ANCA-associated vasculitis: The pneumovas pilot 1 study. Joint Bone Spine 2017;84:643-4.  Back to cited text no. 69
Jeffs LS, Peh CA, Jose MD, Lange K, Hurtado PR. Randomized trial investigating the safety and efficacy of influenza vaccination in patients with antineutrophil cytoplasmic antibody-associated vasculitis. Nephrology (Carlton) 2015;20:343-51.  Back to cited text no. 70
Furer V, Rondaan C, Heijstek MW, Agmon-Levin N, van Assen S, Bijl M, et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis 2019. pii: annrheumdis-2019-215882.  Back to cited text no. 71
Wijetilleka S, Mukhtyar C, Jayne D, Ala A, Bright P, Chinoy H, et al. Immunoglobulin replacement for secondary immunodeficiency after B-cell targeted therapies in autoimmune rheumatic disease: Systematic literature review. Autoimmun Rev 2019;18:535-41.  Back to cited text no. 72
van Daalen EE, Rizzo R, Kronbichler A, Wolterbeek R, Bruijn JA, Jayne DR, et al. Effect of rituximab on malignancy risk in patients with ANCA-associated vasculitis. Ann Rheum Dis 2017;76:1064-9.  Back to cited text no. 73
Ntatsaki E, Carruthers D, Chakravarty K, D'Cruz D, Harper L, Jayne D, et al. BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology (Oxford) 2014;53:2306-9.  Back to cited text no. 74
Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis 2016;75:1583-94.  Back to cited text no. 75
McGeoch L, Twilt M, Famorca L, Bakowsky V, Barra L, Benseler S, et al. CanVasc recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides – Executive summary. Can J Kidney Health Dis 2015;2:43.  Back to cited text no. 76
Souza AW, Calich AL, Mariz HA, Ochtrop ML, Bacchiega AB, Ferreira GA, et al. Recommendations of the Brazilian Society of Rheumatology for the induction therapy of ANCA-associated vasculitis. Rev Bras Reumatol Engl Ed 2017;57 Suppl 2:484-96.  Back to cited text no. 77
Harigai M, Nagasaka K, Amano K, Bando M, Dobashi H, Kawakami T, et al. 2017 clinical practice guidelines of the Japan Research Committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis. Mod Rheumatol 2019;29:20-30.  Back to cited text no. 78
Pagnoux C, Carette S, Khalidi NA, Walsh M, Hiemstra TF, Cuthbertson D, et al. Comparability of patients with ANCA-associated vasculitis enrolled in clinical trials or in observational cohorts. Clin Exp Rheumatol 2015;33:S-77-83.  Back to cited text no. 79


  [Table 1], [Table 2]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Search Strategy
Remission Induct...
Remission Mainte...
Long-Term Outcom...
Guidelines for A...
Article Tables

 Article Access Statistics
    PDF Downloaded225    
    Comments [Add]    

Recommend this journal